后期促进复合物合成泛素链的机理
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摘要
后期促进复合物(APC)是一种E3泛素连接酶,它通过连续地对一系列细胞周期调节子进行泛素化和对蛋白酶体降解而调控细胞周期中的有丝分裂期和G1期。我们对APC合成泛素链的机理及其形成泛素链的构型尚不清楚。因此,我们设计了一个简化的泛素化反应体系,即合成只具有单个泛素化位点的APC底物,其使得APC泛素化反应产物的分析和鉴定变得相对简单。利用这个简化的泛素化反应体系,我们研究了在APC底物上形成泛素链的构型分布。结果发现,APC催化的泛素化反应优先选择形成由泛素赖氨酸残基11所连接的泛素链,并且发现这种泛素链对底物的降解至关重要。进一步研究发现,APC泛素化反应形成这一特定类型的泛素链的原因是在反应体系中存在着一个以前未被发现的泛素交联酶Ube2S,Ube2S在APC泛素化反应中的功能是延长泛素链的长度。结果提示,APC需要通过两步反应来合成长的聚泛素链,底物先被UbcH10或者UbcH5进行单泛素化,然后由Ube2S增加聚泛素链的长度。我们发现Ube2S可以与APC共纯化,并且显性负面的Ube2S突变体减慢了APC底物在细胞溶解液中的降解速度。因此,我们认为Ube2S是APC泛素化通路中的一个重要的新成员。
Background:
During protein ubiquitination a lysine residue on a target protein is conjugated to ubiquitin through an enzymatic cascade involving E1 activating enzymes, E2 conjugating enzymes and E3 ligases. Ubiquitin chain formation can proceed in the same manner by repetitively adding ubiquitins to one or more of seven lysines on the conjugated ubiquitin, potentially generating ubiquitin chains of several different topologies. The linkage, topology, and length of the ubiquitin chains determine the fate of the tagged protein. The Anaphase Promoting Complex (APC) is a multi-subunit E3 enzyme that controls cell cycle progression during mitosis and G1 phase by targeting many cell cycle regulators for degradation. Two activator proteins, Cdc20 and Cdh1 collaborate with APC throughout mitosis and G1 phase in substrate binding and targeting. While the function of APC in cell cycle control is well understood, how this enzymatic complex assembles ubiquitin conjugates on its substrates has been difficult to determine. Under this background, we decided to study the mechanism of ubiquitin chain assembly by APC in detail.
Methods:
1. Degradation assay in cell extracts was used to determine the rates of different APC substrates degradation, and how different components of the pathway affect the activity of APC.
2. In vitro ubiquitination reaction combined with autoradiography was used to determine the lengthes and distribution of ubiquitin chains generated on APC substrates.
3. Immunoprecipitation and Western blot were used to study the protein interactions between APC and other proteins.
Results:
1. Securin with a single lysine can support efficient APC dependent degradation To simplify study of the ubiquitination reactions of APC, we made a construct of securin that allows only a single ubiquitin chain to be formed.
1.1 We first made a lysine-less version of securin (securin-K0) by mutating all of its 20 lysine residues to arginines. This protein is stable in G1 phase cell extracts and unable to be ubiquitinated in an in vitro ubiquitination reaction using purified APC.
1.2 We then added back different lysine residues to the protein and the various securin constructs with single lysines were assayed for their rate of degradation in cell extracts, in comparison to the wildtype protein. Among the mutants, securin-K48 was degraded with kinetics most similar to that of the wildtype securin.
1.3 Degradation of securin-K48 was blocked by the APC inhibitor, Emi1, thus excluding non-specific proteolysis in the extracts system used.
1.4 In in vitro ubiquitination reactions using purified APC and methylated ubiquitin, only one ubiquitin was added to securin-K48, whereas as least 5 ubiquitins were added to the wildtype protein.
1.5 The D-box mutant (DBM) of securin-K48 (securin-K48-DBM) was stable in the cell extracts (Figure 1D), as has been shown for the DBM of wildtype securin.
2. A preference for K-11 linkage in APC catalyzed ubiquitin chain assembly We examined ubiquitination products generated with purified APC, E1, E2s (UbcH10 or UbcH5a), purified securin-K48 and a series of ubiquitin mutants, each containing all but one of its lysine residues converted to arginine.
2.1 Ubiquitin K11 generates the longest ubiquitin chain (>6 ubiquitin molecules) on securin-K48 substrate. Wildtype ubiquitin appeared to give somewhat longer chains. Reactions with linkages made through the K6, K27, K29 or K33 of ubiquitin formed short di or tri-ubiquitinated products, with the mono-ubiquitinated species being the predominant product. Reactions with linkages made through K48 and K63 of ubiquitin formed products with slightly longer ubiquitin chains.
2.2 When securin-K48-DBM was used, the linkage preferences were almost the same, but the products had comparatively shorter ubiquitin chains.
2.3 The linkage preferences in both of the N-terminal fragment of cyclin B1 (N-cyclin B1) mutants were similar to that of securin-K48.
2.4 Quantitation of the average lengths of ubiquitin chains in the products obtained with different ubiquitin mutants on securin-K48 and N-cyclin B1-K20 showed very similar pattern.
2.5 APC dependent ubiquitination can be mediated by both UbcH10 and UbcH5 E2 enzymes. Regardless of the E2 used, K11 is the preferred linkage on both securin-K48 and cyclin B1-K20.
2.6 Adding K48R or K63R ubiquitin mutants has no effect on securin-K48 degradation in G1 extracts, compared with adding the wildtype ubiquitin; by contrast, adding K11R ubiquitin significantly inhibited securin-K48 degradation to the same extent as adding lysine-free ubiquitin (K0 ubiquitin).
3. The role of E2-25K in APC dependent reactions
The E2-25K conjugating enzyme (also know as UbcH1) has recently been shown to mediate the assembly of long ubiquitin chains on APC substrates in conjunction with UbcH10 in yeast. They also extended this model to human cells. We have examined the role of E2-25K in APC catalyzed ubiquitin chain assembly in our experimental system using N-cyclin B1-K20 as a single lysine substrate for ubiquitination.
3.1 When high concentrations of UbcH10 and E2-25K were combined in the same reaction, together, a complete conversion of the substrate and formation of products with very long ubiquitin chains were observed (lane 7 and 8), demonstrating a synergism between UbcH10 and E2-25K, as reported.
3.2 At high concentrations of E2-25K there was no evidence that the elongation of ubiquitin chains catalyzed by E2-25K was dependent on APC.
3.3 When used at these lower concentrations, E2-25K alone was unable to drive any noticeable ubiquitination in the presence or absence of APC; more importantly, it did not act synergistically with UbcH10.
4. Ube2S assembles K-11 linked ubiquitin chains on APC substrates
4.1 We tested whether Ube2S could support APC-catalyzed ubiquitination reaction in our in vitro system. Purified recombinant Ube2S, unlike UbcH10 and UbcH5a, could not support APC-catalyzed ubiquitination on securin-K48. Interestingly, when added in combination with UbcH10 or UbcH5, Ube2S supported formation of much longer ubiquitin chains on the single lysine substrate.
4.2 Securin-K48 was ubiquitinated with APC and UbcH10 first, then APC was removed from the reaction mixture and Ube2S was added. Longer ubiquitin chains were produced when APC was present through the entire course of the reaction. When APC was present only at early stages, the chains were shorter. Ubiquitination reactions with either APC/Cdc20 purified from mitotic extracts or with APC/Cdh1 purified from G1 extracts were indistinguishable.
4.3 We found that Ube2S efficiently copurifies with APC during immunoaffinity purification from HeLa cells extracted under normal conditions, using washes with low salt buffers. However, under a high salt wash conditions, very little Ube2S copurifies with APC. While APC purified under the low salt conditions forms long ubiquitin chains (>4 ubiquitins), APC purified under the high salt condition makes mostly mono-ubiquitinated products.
4.4 In reactions where Ube2S was present, long ubiquitin chains were formed when wild type ubiquitin or ubiquitin mutants other than the ubiquitin K11R were present. However in the reactions with UbK11R, only short ubiquitin chains were produced and addition of Ube2S did not change their length. Thus the ubiquitin chains formed in an APC/UbcH10/Ube2S catalyzed reaction are linked exclusively through K11. 4.5 Reactions with wildtype Ube2S make long ubiquitin chains with a K11 linkage specificity; however, reactions with the C95S mutant of Ube2S not only produce short ubiquitin chains, but also lose the linkage specificity, as three different K/R ubiquitin mutants generate similar products. Reactions including the Ube2SΔC mutant (Ube2S with the C-terminal domain truncated) generated products similar to those of reaction with UbcH10 alone and the linkage specificity of the ubiquitin chains is maintained. 4.6 Securin-K48 was first ubiquitinated with APC and GST-UbcH5a. APC and GST-UbcH5a were then immuno-depleted from the reaction mixture; the ubiquitinated product of this reaction served as substrate for a second reaction with APC and Ube2S. Under these conditions APC and UbcH5 generated mostly mono-ubiquitinated securin-K48. When both APC and Ube2S were added for the second reaction, the mono-ubiquitinated substrate was converted to products with long ubiquitin chains. However, no additional ubiquitin chains were produced in the presence of APC and Ube2S C95S. Ube2SΔC did convert the substrates to products with longer ubiquitin chains, though not as long as those seen in the presence of wildtype Ube2S.
5. The role of Ube2S in substrate degradation
5.1 Both securin and geminin remain stable in extracts made from nocodazole-arrested cells. Addition of Ube2S or Ube2S C95S to this extract system had no effect on the degradation of APC substrates, unlike the addition of UbcH10, which drives the system into anaphase and activates APC.
5.2 Though the rate of degradation of securin and geminin remain the same on addition of wildtype Ube2S to UbcH10-activated extracts, addition of Ube2S C95S delays degradation.
5.3 Longer ubiquitin chains were formed on substrates that were incubated in extracts supplemented with wildtype Ube2S compared to the C95S mutant. The equivalent results were also observed for cyclin B1.
5.4 Ube2S also collaborates with UbcH10 during G1. Securin and geminin are quickly degraded in G1 extracts. Addition of Ube2S C95S into the G1 extracts inhibited the degradation of securin and geminin, though addition of additional Ube2S had no measurable effect.
Conclusion:
1. APC substrates that has only one ubiquitination site can be efficiently ubiquitinated, and this provide a simplified model substrate for studying the formation of a single ubiquitin chain.
2. APC ubiquitination reaction preferentially forms K-11 linked ubiquitin chains, and K-11 linked ubiquitin chain can lead to efficient substrate degradation by the proteasome.
3. A new ubiquitin conjugating enzyme (E2) Ube2S extends the ubiquitin chain in APC catalyzed ubiquitin chain formation, and it also determines the linkage specificity.
4. APC assembles long ubiquitin chain on its substrates in two steps. The first step requires E2 UbcH10 or UbcH5, they monoubiquitinates substrate on multiple lysine residues; the second step requires E2 Ube2S, starting from a ubiquitin that has been coupled to substrate, it forms long ubiquitin chains that are linked only through K-11. This kind of mechanism might be a general mechanism that applies to different ubiquitin ligases (E3), which generates ubiquitin chains of different linkages.
Background:
During protein ubiquitination a lysine residue on a target protein is conjugated to ubiquitin through an enzymatic cascade involving E1 activating enzymes, E2 conjugating enzymes and E3 ligases. Ubiquitin chain formation can proceed in the same manner by repetitively adding ubiquitins to one or more of seven lysines on the conjugated ubiquitin, potentially generating ubiquitin chains of several different topologies. The linkage, topology, and length of the ubiquitin chains determine the fate of the tagged protein. The Anaphase Promoting Complex (APC) is a multi-subunit E3 enzyme that controls cell cycle progression during mitosis and G1 phase by targeting many cell cycle regulators for degradation. Two activator proteins, Cdc20 and Cdh1 collaborate with APC throughout mitosis and G1 phase in substrate binding and targeting. While the function of APC in cell cycle control is well understood, how this enzymatic complex assembles ubiquitin conjugates on its substrates has been difficult to determine. Under this background, we decided to study the mechanism of ubiquitin chain assembly by APC in detail.
Methods:
1. Degradation assay in cell extracts was used to determine the rates of different APC substrates degradation, and how different components of the pathway affect the activity of APC.
2. In vitro ubiquitination reaction combined with autoradiography was used to determine the lengthes and distribution of ubiquitin chains generated on APC substrates.
3. Immunoprecipitation and Western blot were used to study the protein interactions between APC and other proteins.
Results:
1. Securin with a single lysine can support efficient APC dependent degradation To simplify study of the ubiquitination reactions of APC, we made a construct of securin that allows only a single ubiquitin chain to be formed.
1.1 We first made a lysine-less version of securin (securin-K0) by mutating all of its 20 lysine residues to arginines. This protein is stable in G1 phase cell extracts and unable to be ubiquitinated in an in vitro ubiquitination reaction using purified APC.
1.2 We then added back different lysine residues to the protein and the various securin constructs with single lysines were assayed for their rate of degradation in cell extracts, in comparison to the wildtype protein. Among the mutants, securin-K48 was degraded with kinetics most similar to that of the wildtype securin.
1.3 Degradation of securin-K48 was blocked by the APC inhibitor, Emi1, thus excluding non-specific proteolysis in the extracts system used.
1.4 In in vitro ubiquitination reactions using purified APC and methylated ubiquitin, only one ubiquitin was added to securin-K48, whereas as least 5 ubiquitins were added to the wildtype protein.
1.5 The D-box mutant (DBM) of securin-K48 (securin-K48-DBM) was stable in the cell extracts (Figure 1D), as has been shown for the DBM of wildtype securin.
2. A preference for K-11 linkage in APC catalyzed ubiquitin chain assembly We examined ubiquitination products generated with purified APC, E1, E2s (UbcH10 or UbcH5a), purified securin-K48 and a series of ubiquitin mutants, each containing all but one of its lysine residues converted to arginine.
2.1 Ubiquitin K11 generates the longest ubiquitin chain (>6 ubiquitin molecules) on securin-K48 substrate. Wildtype ubiquitin appeared to give somewhat longer chains. Reactions with linkages made through the K6, K27, K29 or K33 of ubiquitin formed short di or tri-ubiquitinated products, with the mono-ubiquitinated species being the predominant product. Reactions with linkages made through K48 and K63 of ubiquitin formed products with slightly longer ubiquitin chains.
2.2 When securin-K48-DBM was used, the linkage preferences were almost the same, but the products had comparatively shorter ubiquitin chains.
2.3 The linkage preferences in both of the N-terminal fragment of cyclin B1 (N-cyclin B1) mutants were similar to that of securin-K48.
2.4 Quantitation of the average lengths of ubiquitin chains in the products obtained with different ubiquitin mutants on securin-K48 and N-cyclin B1-K20 showed very similar pattern.
2.5 APC dependent ubiquitination can be mediated by both UbcH10 and UbcH5 E2 enzymes. Regardless of the E2 used, K11 is the preferred linkage on both securin-K48 and cyclin B1-K20.
2.6 Adding K48R or K63R ubiquitin mutants has no effect on securin-K48 degradation in G1 extracts, compared with adding the wildtype ubiquitin; by contrast, adding K11R ubiquitin significantly inhibited securin-K48 degradation to the same extent as adding lysine-free ubiquitin (K0 ubiquitin).
3. The role of E2-25K in APC dependent reactions
The E2-25K conjugating enzyme (also know as UbcH1) has recently been shown to mediate the assembly of long ubiquitin chains on APC substrates in conjunction with UbcH10 in yeast. They also extended this model to human cells. We have examined the role of E2-25K in APC catalyzed ubiquitin chain assembly in our experimental system using N-cyclin B1-K20 as a single lysine substrate for ubiquitination.
3.1 When high concentrations of UbcH10 and E2-25K were combined in the same reaction, together, a complete conversion of the substrate and formation of products with very long ubiquitin chains were observed (lane 7 and 8), demonstrating a synergism between UbcH10 and E2-25K, as reported.
3.2 At high concentrations of E2-25K there was no evidence that the elongation of ubiquitin chains catalyzed by E2-25K was dependent on APC.
3.3 When used at these lower concentrations, E2-25K alone was unable to drive any noticeable ubiquitination in the presence or absence of APC; more importantly, it did not act synergistically with UbcH10.
4. Ube2S assembles K-11 linked ubiquitin chains on APC substrates
4.1 We tested whether Ube2S could support APC-catalyzed ubiquitination reaction in our in vitro system. Purified recombinant Ube2S, unlike UbcH10 and UbcH5a, could not support APC-catalyzed ubiquitination on securin-K48. Interestingly, when added in combination with UbcH10 or UbcH5, Ube2S supported formation of much longer ubiquitin chains on the single lysine substrate.
4.2 Securin-K48 was ubiquitinated with APC and UbcH10 first, then APC was removed from the reaction mixture and Ube2S was added. Longer ubiquitin chains were produced when APC was present through the entire course of the reaction. When APC was present only at early stages, the chains were shorter. Ubiquitination reactions with either APC/Cdc20 purified from mitotic extracts or with APC/Cdh1 purified from G1 extracts were indistinguishable.
4.3 We found that Ube2S efficiently copurifies with APC during immunoaffinity purification from HeLa cells extracted under normal conditions, using washes with low salt buffers. However, under a high salt wash conditions, very little Ube2S copurifies with APC. While APC purified under the low salt conditions forms long ubiquitin chains (>4 ubiquitins), APC purified under the high salt condition makes mostly mono-ubiquitinated products.
4.4 In reactions where Ube2S was present, long ubiquitin chains were formed when wild type ubiquitin or ubiquitin mutants other than the ubiquitin K11R were present. However in the reactions with UbK11R, only short ubiquitin chains were produced and addition of Ube2S did not change their length. Thus the ubiquitin chains formed in an APC/UbcH10/Ube2S catalyzed reaction are linked exclusively through K11. 4.5 Reactions with wildtype Ube2S make long ubiquitin chains with a K11 linkage specificity; however, reactions with the C95S mutant of Ube2S not only produce short ubiquitin chains, but also lose the linkage specificity, as three different K/R ubiquitin mutants generate similar products. Reactions including the Ube2SΔC mutant (Ube2S with the C-terminal domain truncated) generated products similar to those of reaction with UbcH10 alone and the linkage specificity of the ubiquitin chains is maintained. 4.6 Securin-K48 was first ubiquitinated with APC and GST-UbcH5a. APC and GST-UbcH5a were then immuno-depleted from the reaction mixture; the ubiquitinated product of this reaction served as substrate for a second reaction with APC and Ube2S. Under these conditions APC and UbcH5 generated mostly mono-ubiquitinated securin-K48. When both APC and Ube2S were added for the second reaction, the mono-ubiquitinated substrate was converted to products with long ubiquitin chains. However, no additional ubiquitin chains were produced in the presence of APC and Ube2S C95S. Ube2SΔC did convert the substrates to products with longer ubiquitin chains, though not as long as those seen in the presence of wildtype Ube2S.
5. The role of Ube2S in substrate degradation
5.1 Both securin and geminin remain stable in extracts made from nocodazole-arrested cells. Addition of Ube2S or Ube2S C95S to this extract system had no effect on the degradation of APC substrates, unlike the addition of UbcH10, which drives the system into anaphase and activates APC.
5.2 Though the rate of degradation of securin and geminin remain the same on addition of wildtype Ube2S to UbcH10-activated extracts, addition of Ube2S C95S delays degradation.
5.3 Longer ubiquitin chains were formed on substrates that were incubated in extracts supplemented with wildtype Ube2S compared to the C95S mutant. The equivalent results were also observed for cyclin B1.
5.4 Ube2S also collaborates with UbcH10 during G1. Securin and geminin are quickly degraded in G1 extracts. Addition of Ube2S C95S into the G1 extracts inhibited the degradation of securin and geminin, though addition of additional Ube2S had no measurable effect.
Conclusion:
1. APC substrates that has only one ubiquitination site can be efficiently ubiquitinated, and this provide a simplified model substrate for studying the formation of a single ubiquitin chain.
2. APC ubiquitination reaction preferentially forms K-11 linked ubiquitin chains, and K-11 linked ubiquitin chain can lead to efficient substrate degradation by the proteasome.
3. A new ubiquitin conjugating enzyme (E2) Ube2S extends the ubiquitin chain in APC catalyzed ubiquitin chain formation, and it also determines the linkage specificity.
4. APC assembles long ubiquitin chain on its substrates in two steps. The first step requires E2 UbcH10 or UbcH5, they monoubiquitinates substrate on multiple lysine residues; the second step requires E2 Ube2S, starting from a ubiquitin that has been coupled to substrate, it forms long ubiquitin chains that are linked only through K-11. This kind of mechanism might be a general mechanism that applies to different ubiquitin ligases (E3), which generates ubiquitin chains of different linkages.
引文
[1] Chau V, Tobias JW, Bachmair A, et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein [J]. Science,1989, 243(4989): 1576–1583.
[2] Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal [J]. EMBO J, 2000,19(1):94–102.
[3] Pickart CM and Fushman D. Polyubiquitin chains: polymeric protein signals [J]. Curr Opin Chem Biol, 2004, 8(6): 610-616
[4] Sun L, Chen ZJ. The novel functions of ubiquitination in signaling [J]. Cur Opin Cell Biol, 2004,16(3):339–340
[5] Varelas X, Ptak C and Ellison MJ. Cdc34 self-association is facilitated by ubiquitin thiolester formation and is required for its catalytic activity [J]. Mol Cel Biol, 2003, 23(15):5388–5400.
[6] Pickart CM and Eddins MJ. Ubiquitin: structures, functions, mechanisms [J]. Biochim Biophys Acta, 2004,1695(1-3):55–72.
[7] Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes [J]. Biochim Biophys Acta, 2004,1695(1-3)189–207.
[8] Nijman SM, Luna-Vargas MP, Velds A, et al. A genomic and functional inventory of deubiquitinating enzymes [J]. Cell, 2005,123(5):773–786.
[9] Rape M, Reddy SK and Kirschner MW. The processivity of multiubiquitination by the APC determines the order of substrate degradation[J].Cell, 2006, 124(1):89-103
[10] Pickart CM. Back to the future with ubiquitin[J].Cell, 2004, 116(2):181–190.
[11] Hicke L and Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins [J]. Annu Rev Cell Dev Biol, 2003,19:141–172.
[12] Wang X, Naidu SR, Sverdrup F, et al. Tax1BP1 interacts with papillomavirus E2 and regulates E2-dependent transcription and stability. [J]. J Virol, 2009, 83(5):2274-84.
[13] Buchberger A. From UBA to UBX: new words in the ubiquitin vocabulary [J]. Trends Cell Biol, 2002, 12(5):216–221.
[14]Hochstrasser M. Evolution and function of ubiquitin-like protein-conjugation systems [J]. Nat Cell Biol, 2000,2(8) :E153–E157.
[15] Adams J. The development of proteasome inhibitors as anticancer drugs [J]. Cancer Cell, 2004, 5(5):417–421.
[16] Chau V, Tobias JW, Bachmair A, et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein [J]. Science,1989, 243(45898):1576–1583.
[17] Finley D, Sadis S, Monia BP, et al. Inhibition of proteolysis and cell cycle progression in a multiubiquitination-deficient yeast mutant [J]. Mol Cell Biol, 1994, 14(8):5501–5509.
[18] Flick K, Ouni I, Wohlschlegel JA, et al. Proteolysis-independent regulation of the transcription factor Met4 by a single Lys48-linked ubiquitin chain [J]. Nat Cell Biol, 2004, 6(7):634–641.
[19] Spence J, Sadis S, Haas AL, et al. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination [J]. Mol Cell Biol,1995,15(3) : 1265–1273.
[20] Arnason T, Ellison MJ. Stress resistance in Saccharomyces cerevisiae is strongly associated with assembly of a novel type of multiubiquitin chain [J]. Mol Cell Biol, 1994,14(12): 7876–7883.
[21]Nishikawa H, Oooka S, Sato K, et al.Mass spectrophotometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase [J]. J Biol Chem, 2004, 279(6): 3916–3924.
[22] Peng J, Schwartz D, Elias JE, et al. A proteomics approach to understanding protein ubiquitination [J]. Nat Biotechnol, 2003, 21(8): 921–926.
[23] Saeki Y, Isono E, Oguchi T, et al. Intracellularly inducible, ubiquitinhydrolase-insensitive tandem ubiquitins inhibit the 26S proteasome activity and cell division [J]. Genes Genet Syst, 2004, 79(2):77–86.
[24]Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal [J]. EMBO J, 2000,19(1): 94–102.
[25] Ryu KS, Lee KJ, Bae SH, et al. Binding surface mapping of intra and inter domain interactions among HHR23B, ubiquitin, and polyubiquitin binding site 2 of S5a [J]. J Biol Chem, 2003, 278(38): 36621–36627.
[26] Wang Q, Goh AM, Howley PM. Ubiquitin recognition by the DNA repair protein hHR23A [J]. Biochemistry, 2003, 42(46): 13529–13535.
[27] Varadan R, Assfalg M, Haririnia A, et al. Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin signaling [J]. J Biol Chem, 2004, 279(8): 7055–7063.
[28] Mueller TD, Kamionka M and Feigon J. Specificity of the interaction between ubiquitin-associated domains and ubiquitin [J]. J Biol Chem, 2004, 279(12): 11926–11936.
[29]Kang RS, Daniels CM, Francis SA, et al. Solution structure of a CUE-monoubiquitin complex reveals a conserved mode of ubiquitin binding [J]. Cell, 2003, 113(5): 621–630.
[30] Alam SL, Sun J, Payne M, et al. Sundquist, Ubiquitin interactions of NZF zinc fingers [J]. EMBO J, 2004,23(7): 1411–1421.
[31] Sundquist WI, Schubert HL, Kelly BN, et al. Ubiquitin recognition by the human TSG101 protein [J]. Mol Cell, 2004, 13(6): 783–789.
[32] Swanson KA, Kang RS, Stamenova SD, et al. Solution structure of Vps27 UIM-ubiquitin complex important for endosomal sorting and receptor downregulation [J]. EMBO J, 2003, 22(18): 4597–4606.
[33] Sloper-Mould KE, Jemc J, Pickart CM. Distinct functional surface regions on ubiquitin [J]. J Biol Chem, 2001, 276(32): 30483–30489.
[34] Phillips CL, Thrower J, Pickart CM, et al. Structure of a new crystal form of tetraubiquitin [J]. Acta Crystallogr D Biol Crystallogr, 2001,57(part 2): 341–344.
[35] Ulrich HD. Degradation or maintenance: actions of the ubiquitin system oneukaryotic chromatin [J]. Eukaryot Cell, 2002, 1(1): 1–10.
[36] Spence J, Gali RR, Dittmar G, et al. Cell cycle-regulated modification of the ribosome by a variant multiubiquitin chain [J]. Cell, 2000, 102(1): 67–76.
[37] Koegl M, Hoppe T, Schlenker S, et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly [J]. Cell, 1999, 96(5): 635–644.
[38] Lindsten K, de Vrij FM, Verhoef LG, et al. Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion protein degradation substrate that blocks proteasomal degradation [J]. J Cell Biol, 2002,157(3): 417–427
[39]Saeki Y, Tayama Y, Toh-e A, et al. Definitive evidence for Ufd2-catalyzed elongation of the ubiquitin chain through Lys48 linkage [J]. Biochem Biophys Res Commun, 2004, 320(3): 840–845.
[40] Baboshina OV, Haas AL. Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26 S proteasome subunit 5 [J]. J Biol Chem, 1996, 271(5): 2823–2831.
[41] Hofmann RM, Pickart CM. In vitro assembly and recognition of Lys-63 polyubiquitin chains [J]. J Biol Chem, 2001, 276(30): 27936–27943.
[42] Peters JM. The anaphase-promoting complex: proteolysis in mitosis and beyond [J]. Mol Cell, 2002, 9(5): 931–943.
[43] Aristarkhov A. Eytan E, Moghe A, et al. E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins [J]. Proc. Natl Acad. Sci. USA,1996, 93(9): 4294–4299
[44]Yu H, King RW, Peters JM, et al. Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation [J]. Curr Biol, 1996, 6(4): 455–466 .
[45]Townsley FM, Aristarkhov A, Beck S, et al. Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase [J]. Proc. Natl Acad. Sci USA, 1997, 94(6): 2362–2367
[46] Seino H, Kishi T, Nishitani H, et al. Two ubiquitin-conjugating enzymes, UbcP1/Ubc4 and UbcP4/Ubc11, have distinct functions for ubiquitination of mitotic cyclin [J]. Mol Cell Biol, 2003, 23(10): 3497–3505.
[47] Mathe E, Kraft C, Giet R, et al. The E2-C vihar is required for the correct spatiotemporal proteolysis of cyclin B and itself undergoes cyclical degradation [J]. Curr Biol, 2004, 14(19): 1723–1733
[48] Townsley FM, Ruderman JV. Functional analysis of the Saccharomyces cerevisiae UBC11 gene [J].Yeast, 1998, 14(8): 747–757
[49] Carroll CW, Morgan DO. The Doc1 subunit is a processivity factor for the anaphase-promoting complex [J]. Nature Cell Biol, 2002, 4(11): 880–887
[50] Schwab M, Neutzner M, MockerD, et al. Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC [J]. EMBO J, 2001, 20(18): 5165–5175
[51] Passmore LA, McCormack EA, Au SW, et al. Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition [J].EMBO J, 2003, 22(4): 786–796
[52] Vodermaier HC, Gieffers C, Maurer-Stroh S, et al.. TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1 [J]. Curr Biol, 2003, 13(17): 1459–1468
[53] Kraft C, Vodermaier HC, Maurer-Stroh S, et al. The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates [J]. Mol. Cell, 2005, 18(5): 543–553
[54] Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway [J]. Nature, 1991, 349(6305): 132–138
[55] Pfleger CM, Kirschner MW. The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1 [J]. Genes Dev, 2000, 14(6): 655–665.
[56] Clute P, Pines J. Temporal and spatial control of cyclin B1 destruction in metaphase [J]. Nature Cell Biol, 1999, 1(2): 82–87
[57] Murray AW, Solomon MJ, Kirschner MW. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity [J]. Nature,1989, 339(6222): 280–286
[58] King RW, Glotzer M, Kirschner MW. Mutagenic analysis of the destructionsignal of mitotic cyclins and structural characterization of ubiquitinated intermediates [J]. Mol. Biol. Cell, 1996, 7(9): 1343–1357
[59] Jeffrey PD, Russo AA, Polyak K, et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex [J]. Nature, 1995, 376(6538): 313–320
[60] Diffley JF. Regulation of early events in chromosome replication [J]. Curr. Biol, 2004, 14(18) R778–R786
[61] McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis [J]. Cell, 1998, 93(6): 1043–1053
[62] Wohlschlegel JA , Dwyer BT, Dhar SK, et al. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1 [J]. Science, 2000, 290(5500): 2309–2312
[63]Tada S, Li A, Maiorano D, et al. Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin [J]. Nature Cell Biol, 2001, 3(2): 107–113
[64] Quinn LM, Herr A, McGarry TJ, et al.The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis [J]. Genes Dev, 2001, 15(20): 2741–2754
[65] Nasmyth K. Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis [J]. Annu. Rev. Genet, 2001, 35: 673–745
[66] Yamamoto A, Guacci V, Koshland D. Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae [J]. J Cell Biol, 1996, 133(1): 85–97
[67] Jallepalli PV, Waizenegger IC, Bunz F, et al. Securin is required for chromosomal stability in human cells [J]. Cell, 2001, 105(4): 445–457
[68] Mei J, Huang X, Zhang P. Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts [J]. Cur Biol, 2001, 11(15): 1197–1201
[69] Wang Z, Yu R, Melmed S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia,aberrant cell cycle progression, and premature centromere division [J]. Mol. Endocrinol, 2001, 15(11): 1870–1879
[70] Stemmann O, Zou H, Gerber SA, et al. Dual inhibition of sister chromatid separation at metaphase [J]. Cell, 2001, 107(6): 715–726
[71] Gorr IH, Boos D, Stemmann O. Mutual inhibition of separase and Cdk1 by two-step complex formation [J]. Mol Cell, 2005,19(1): 135–141
[72] Shteinberg M, Protopopov Y, Listovsky T, et al. A. Phosphorylation of the cyclosome is required for its stimulation by Fizzy/Cdc20 [J]. Biochem. Biophys. Res Commun, 1999, 260(1): 193–198
[73] Kramer ER, Scheuringer N, Podtelejnikov AV, et al. Mitotic regulation of the APC activator proteins CDC20 and CDH1 [J]. Mol Biol Cell, 2000, 11(5): 1555–1569
[74] Rudner AD, Murray AW. Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex [J]. J. Cell Biol, 2000, 149(7): 1377–1390
[75] Golan A, Yudkovsky Y, Hershko A. The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1–cyclin B and Plk [J]. J Biol Chem, 2002, 2779(18): 15552–15557
[76] Kraft C, Herzog F, Gieffers C, et al. Mitotic regulation of the human anaphase-promoting complex by phosphorylation [J]. EMBO J, 2003, 22(24): 6598–6609
[77] Zachariae W, Schwab M, Nasmyth K, et al. Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex [J]. Science, 1998, 282(5394): 1721–1724
[78] Jaspersen SL, Charles JF, Morgan DO. Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14 [J]. Curr Biol, 1999, 9(5): 227–236
[79] Blanco MA, Sanchez-Diaz A, de Prada JM, et al. APCSte9/Srw1 promotes degradation of mitotic cyclins in G1 and is inhibited by Cdc2 phosphorylation [J]. EMBO J, 2000, 19(15): 3945–3955
[80] Yamaguchi S, Okayama H, Nurse P. Fission yeast Fizzy-related protein Srw1p is a G1-specific promoter of mitotic cyclin B degradation [J]. EMBO J, 2000, 19(15): 3968–3977
[81] Visintin R, Craig K, Hwang ES, et al. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation [J].Mol. Cell, 1998, 2(6): 709–718
[82] Hagting A, Den Elzen N, Vodermaier HC, et al. Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1 [J].J. Cell Biol, 2002, 157(7): 1125–1137
[83] Prinz S, Hwang ES, Visintin R, et al. The regulation of Cdc20 proteolysis reveals a role for APC components Cdc23 and Cdc27 during S phase and early mitosis [J]. Curr Biol, 1998, 8(13): 750–760
[84] Shirayama M, Zachariae W, Ciosk R, et al. The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/Fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae [J].EMBO J, 1998, 17(5):1336–1349
[85] Sorensen CS, Lukas C, Kramer ER, et al. Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis [J]. Mol Cell Biol, 2000, 20(20): 7613–7623
[86] Huang JN, Park I, Ellingson E, et al. Activity of the APCCdh1 form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p [J].J Cell Biol, 2001, 154(1): 85–94
[87] Knoblich JA, Sauer K, Jones L, et al. Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation [J]. Cell, 1994, 77(1): 107–120
[88] Dong X, Zavitz KH, Thomas BJ, et al. Control of G1 in the developing Drosophila eye: Rca1 regulates Cyclin A [J]. Genes Dev, 1997, 11(1): 94–105
[89] Grosskortenhaus R, Sprenger F. Rca1 inhibits APC–Cdh1Fzr and is required to prevent cyclin degradation in G2 [J].Dev. Cell, 2002, 2: 29–40
[90] Lukas C, S?rensen CS, Kramer E, et al. Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex [J].Nature, 1999, 401(6755): 815–818
[91] Hsu JY, Reimann JD, Sorensen CS, et al.E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1 [J]. Nature Cell Biol, 2002, 4(5): 358–366
[92] Reimann JD, Gardner BE, Margottin-Goguet F, et al. Emi1 regulates the anaphase-promoting complex by a different mechanism than Mad2 proteins [J]. Genes Dev, 2001, 15(24): 3278–3285
[93] Rape M, Kirschner MW. Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry [J]. Nature, 2004, 432(7017): 588–595
[94] Yamanaka A, Hatakeyama S, Kominami K, et al. Cell cycle-dependent expression of mammalian E2-C regulated by the anaphase-promoting complex/cyclosome [J]. Mol Biol Cell, 2000, 11(8): 2821–2831
[95] Benmaamar R, Pagano M. Involvement of the SCF complex in the control of Cdh1 degradation in S-phase [J]. Cell Cycle, 2005, 4(9): 1230–1232
[96] Elzen den N, Pines J. Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase [J]. J Cell Biol, 2001, 153(1): 121–136
[97] Geley S, Kramer E, Gieffers C, et al. Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint [J].J. Cell Biol, 2001, 153(1): 137–148
[98] Hames RS, Wattam SL, Yamano H, et al. APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box [J].EMBO J, 2001, 20(24): 7117–7127
[99] Rieder CL, Schultz A, Cole R, et al. Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle [J]. J Cell Biol, 1994, 127(5): 1301–1310
[100]Rieder CL, Cole RW, Khodjakov A, et al. The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores [J]. J. Cell Biol, 1995, 130(4): 941–948
[101]Musacchio A, Hardwick KG. The spindle checkpoint: structural insightsinto dynamic signalling [J]. Nature Rev. Mol. Cell Biol, 2002, 3(10) 731–741
[102]Li Y, Gorbea C, Mahaffey D, et al. MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity [J]. Proc. Natl Acad. Sci. USA, 1997, 94(23): 12431–12436
[103]Fang G, Yu H, Kirschner MW. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation [J]. Genes Dev, 1998, 12(12): 1871–1883
[104]Hwang LH, Lau LF, Smith DL, et al. Budding yeast Cdc20: a target of the spindle checkpoint [J]. Science, 1998, 279(5335): 1041–1044
[105]Kim SH, Lin DP, Matsumoto S, et al. Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint [J]. Science, 1998, 279(5353): 1045–1047
[106]Sudakin V, Chan GK, Yen TJ. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2 [J]. J. Cell Biol, 2001, 154(5): 925–936
[107]Tang Z, Bharadwaj R, Li B, et al. Mad2-independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1 [J]. Dev Cell, 2001,1(2): 227–237
[108]Fang G. Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex [J]. Mol. Biol. Cell, 2002, 13(3): 755–766
[109]Sironi L, Melixetian M, Faretta M, et al. Mad2 binding to Mad1 and Cdc20, rather than oligomerization, is required for the spindle checkpoint [J]. EMBO J, 2001, 20(22): 6371–6382
[110]Luo X, Tang Z, Rizo J, et al. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20 [J]. Mol. Cell, 2002, 9(1): 59–71
[111]Sironi L , Mapelli M, Knapp S, et al. Crystal structure of the tetrameric Mad1–Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint [J]. EMBO J, 2002, 21(10): 2496–2506
[112]Shah JV , Botvinick E, Bonday Z, et al. Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing [J]. CurrBiol, 2004 14(11): 942–952
[113]De Antoni, Pearson CG, Cimini D, et al. The Mad1–Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint [J]. Curr Biol, 2005, 15(3): 214–225
[114]Fraschini R , Beretta A, Sironi L, et al. Bub3 interaction with Mad2, Mad3 and Cdc20 is mediated by WD40 repeats and does not require intact kinetochores [J]. EMBO J, 2001, 20(23): 6648–6659
[115]Shirayama M, Toth A, Galova M, et al. APCCdc20 promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5 [J].Nature, 1999, 402(6758): 203–207
[116]Schwab M, Lutum AS, Seufert W. Yeast Hct1 is a regulator of Clb2 cyclin proteolysis [J]. Cell, 1997, 90(4): 683–693
[117]Visintin R, Prinz S, Amon A. CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis [J].Science, 1997, 278(5337): 460–463
[118]Rape M, Reddy SK, Kirschner MW. The processivity of multiubiquitination by the APC determines the order of substrate degradation [J]. Cell, 2006, 124(1): 89–103
[119]Hayes MJ, Kimata Y, Wattam SL, et al. Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C [J]. Nature Cell Biol, 2006, 8(6): 607–614
[120]Kallio M, Weinstein J, Daum JR, et al. Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events [J]. J. Cell Biol, 1998, 141(6): 1393–1406
[121]Wassmann K, Benezra R. Mad2 transiently associates with an APC–p55Cdc complex during mitosis [J]. Proc. Natl Acad. Sci. USA, 1998, 95(19): 11193–11198
[122]Chan GK, Jablonski SA, Sudakin V, et al. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds thecyclosome/APC [J].J Cell Biol, 1999, 146(5): 941–954
[123]Morrow CJ, Tighe A, Johnson VL, et al. Bub1 and Aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20 [J]. J Cell Sci, 2005, 118(16): 3639–3652
[124]Pickart CM, Cohen RE. Proteasomes and their kin: proteases in the machine age [J]. Na. Rev Mol Cell Biol, 2004, 5(3): 177–187.
[1]Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms [J]. Biochim Biophys Acta, 2004, 1695(1-3): 55-72.
[2]Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular signals [J]. EMBO Rep, 2008, 9(6): 536-542.
[3]Peng J, Schwartz D, Elias JE, et al. A proteomics approach to understanding protein ubiquitination [J]. Nature Biotechnol, 2003, 21(8): 921-926.
[4]Pickart CM, Fushman D. Polyubiquitin chains: polymeric protein signals [J]. Curr Opin Chem Biol, 2004, 8(6): 610–616.
[5]Visintin R, Prinz S, Amon A. CDC20 and CDH1: a family of substrate specific activators of APC-dependent proteolysis [J]. Science, 1997, 278(5337): 460-463.
[6]Rape M, Reddy SK, Kirschner MW. The processivity of multiubiquitination by the APC determines the order of substrate degradation [J]. Cell, 2006, 124(1): 89-103.
[7]Hochstrasser M. Lingering mysteries of ubiquitin-chain assembly [J]. Cell, 2006, 124(1): 27-34.
[8]Rodrigo-Brenni MC, Morgan DO. Sequential E2s drive polyubiquitin chain assembly on APC targets [J]. Cell, 2007, 130(1): 127-139.
[9]Kirkpatrick DS, Hathaway NA, Hanna J, et al. Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology [J]. Nature Cell Biol, 2006, 8(7): 700-710.
[10]Petroski MD, Deshaies RJ. Context of multiubiquitin chain attachment influences the rate of Sic1 degradation [J]. Mol. Cell, 2003, 11(6): 1435-1444.
[11]King RW, Glotzer M, Kirschner MW. Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates [J]. Mol. Biol. Cell, 1996, 7(9): 1343-1357.
[12]Zou H, McGarry TJ, Bernal T, et al. Identification of a VertebrateSister-Chromatid Separation Inhibitor Involved in Transformation and Tumorigenesis [J]. Science, 1999, 285(5426): 418-422.
[13]Aristarkhov A, Eytan E, Moghe A, et al. E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins [J]. Proc. Natl. Acad. Sci. USA , 1996, 93(9): 4294-4299.
[14]Yu H, King RW, Peters JM, et al. Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation [J]. Curr Biol, 1996, 6(4): 455-466.
[15]Chen Z, Pickart CM. A 25-kilodalton ubiquitin carrier protein (E2) catalyzes multiubiquitin chain synthesis via lysine 48 of ubiquitin [J]. J Biol Chem, 1990, 265(35): 21835-21842.
[16]Pickart CM, Vella AT. Levels of active ubiquitin carrier proteins decline during Erythroid maturation [J]. J Biol Chem, 1988, 263(24): 12028-12035.
[17]Liu Z, Diaz LA, Haas AL, et al. cDNA cloning of a novel human ubiquitin carrier protein. An antigenic domain specifically recognized by endemic pemphigus foliaceus autoantibodies is encoded in a secondary reading frame of this human epidermal transcript [J]. J Biol Chem, 1992, 267(22): 15829-15835.
[18]Baboshina OV, Haas AL. Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26 S proteasome subunit 5 [J]. J Biol Chem, 1996, 271(5): 2823-2831.
[19]Tedesco D, Zhang J, Trinh L, et al. The ubiquitin-conjugating enzyme E2-EPF is overexpressed in primary breast cancer and modulates sensitivity to topoisomerase II inhibition [J]. Neoplasia, 2007, 9(7): 601-613.
[20]Braunstein I, Miniowitz S, Moshe Y, et al. Inhibitory factors associated with anaphase-promoting complex/cylosome in mitotic checkpoint [J]. Proc Natl Acad Sci, 2007, 104(12): 4870-4875.
[21]Reddy SK, Rape M, Kirschner MW. Ubiquitination by the anaphasepromoting complex drives spindle checkpoint inactivation [J]. Nature, 2007, 446(7138): 921-925.
[22]Summers MK, Pan B, Mukhyala K, et al. The unique N terminus of the UbcH10 E2 enzyme controls the threshold for APC activation and enhances checkpoint regulation of the APC [J]. Mol Cell, 2008, 31(4): 544-556.
[23]Alexandru G., Graumann J, Smith GT, et al. UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover [J]. Cell, 2008, 134(5): 804-816.
[24]Bennett EJ, Shaler TA, Woodman B, et al. Global changes to the ubiquitin system in Huntington's disease [J]. Nature, 2007, 448(7154): 704–708.
[25]Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal [J]. EMBO J, 2000, 19(1): 94-102.
[26]Christensen DE, Brzovic PS, Klevit RE. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages [J]. Nat. Struct. Mol. Biolm 2007, 14(10): 941-948.
[27]Windheim M, Peggie M, Cohen P. Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology [J]. Biochem J, 2008, 409(3): 723-729.
[28]Jin L, Williamson A, Banerjee S, Philipp I, Rape M. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex [J]. Cell, 2008, 133(4):653-665.
[2] Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal [J]. EMBO J, 2000,19(1):94–102.
[3] Pickart CM and Fushman D. Polyubiquitin chains: polymeric protein signals [J]. Curr Opin Chem Biol, 2004, 8(6): 610-616
[4] Sun L, Chen ZJ. The novel functions of ubiquitination in signaling [J]. Cur Opin Cell Biol, 2004,16(3):339–340
[5] Varelas X, Ptak C and Ellison MJ. Cdc34 self-association is facilitated by ubiquitin thiolester formation and is required for its catalytic activity [J]. Mol Cel Biol, 2003, 23(15):5388–5400.
[6] Pickart CM and Eddins MJ. Ubiquitin: structures, functions, mechanisms [J]. Biochim Biophys Acta, 2004,1695(1-3):55–72.
[7] Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes [J]. Biochim Biophys Acta, 2004,1695(1-3)189–207.
[8] Nijman SM, Luna-Vargas MP, Velds A, et al. A genomic and functional inventory of deubiquitinating enzymes [J]. Cell, 2005,123(5):773–786.
[9] Rape M, Reddy SK and Kirschner MW. The processivity of multiubiquitination by the APC determines the order of substrate degradation[J].Cell, 2006, 124(1):89-103
[10] Pickart CM. Back to the future with ubiquitin[J].Cell, 2004, 116(2):181–190.
[11] Hicke L and Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins [J]. Annu Rev Cell Dev Biol, 2003,19:141–172.
[12] Wang X, Naidu SR, Sverdrup F, et al. Tax1BP1 interacts with papillomavirus E2 and regulates E2-dependent transcription and stability. [J]. J Virol, 2009, 83(5):2274-84.
[13] Buchberger A. From UBA to UBX: new words in the ubiquitin vocabulary [J]. Trends Cell Biol, 2002, 12(5):216–221.
[14]Hochstrasser M. Evolution and function of ubiquitin-like protein-conjugation systems [J]. Nat Cell Biol, 2000,2(8) :E153–E157.
[15] Adams J. The development of proteasome inhibitors as anticancer drugs [J]. Cancer Cell, 2004, 5(5):417–421.
[16] Chau V, Tobias JW, Bachmair A, et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein [J]. Science,1989, 243(45898):1576–1583.
[17] Finley D, Sadis S, Monia BP, et al. Inhibition of proteolysis and cell cycle progression in a multiubiquitination-deficient yeast mutant [J]. Mol Cell Biol, 1994, 14(8):5501–5509.
[18] Flick K, Ouni I, Wohlschlegel JA, et al. Proteolysis-independent regulation of the transcription factor Met4 by a single Lys48-linked ubiquitin chain [J]. Nat Cell Biol, 2004, 6(7):634–641.
[19] Spence J, Sadis S, Haas AL, et al. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination [J]. Mol Cell Biol,1995,15(3) : 1265–1273.
[20] Arnason T, Ellison MJ. Stress resistance in Saccharomyces cerevisiae is strongly associated with assembly of a novel type of multiubiquitin chain [J]. Mol Cell Biol, 1994,14(12): 7876–7883.
[21]Nishikawa H, Oooka S, Sato K, et al.Mass spectrophotometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase [J]. J Biol Chem, 2004, 279(6): 3916–3924.
[22] Peng J, Schwartz D, Elias JE, et al. A proteomics approach to understanding protein ubiquitination [J]. Nat Biotechnol, 2003, 21(8): 921–926.
[23] Saeki Y, Isono E, Oguchi T, et al. Intracellularly inducible, ubiquitinhydrolase-insensitive tandem ubiquitins inhibit the 26S proteasome activity and cell division [J]. Genes Genet Syst, 2004, 79(2):77–86.
[24]Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal [J]. EMBO J, 2000,19(1): 94–102.
[25] Ryu KS, Lee KJ, Bae SH, et al. Binding surface mapping of intra and inter domain interactions among HHR23B, ubiquitin, and polyubiquitin binding site 2 of S5a [J]. J Biol Chem, 2003, 278(38): 36621–36627.
[26] Wang Q, Goh AM, Howley PM. Ubiquitin recognition by the DNA repair protein hHR23A [J]. Biochemistry, 2003, 42(46): 13529–13535.
[27] Varadan R, Assfalg M, Haririnia A, et al. Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin signaling [J]. J Biol Chem, 2004, 279(8): 7055–7063.
[28] Mueller TD, Kamionka M and Feigon J. Specificity of the interaction between ubiquitin-associated domains and ubiquitin [J]. J Biol Chem, 2004, 279(12): 11926–11936.
[29]Kang RS, Daniels CM, Francis SA, et al. Solution structure of a CUE-monoubiquitin complex reveals a conserved mode of ubiquitin binding [J]. Cell, 2003, 113(5): 621–630.
[30] Alam SL, Sun J, Payne M, et al. Sundquist, Ubiquitin interactions of NZF zinc fingers [J]. EMBO J, 2004,23(7): 1411–1421.
[31] Sundquist WI, Schubert HL, Kelly BN, et al. Ubiquitin recognition by the human TSG101 protein [J]. Mol Cell, 2004, 13(6): 783–789.
[32] Swanson KA, Kang RS, Stamenova SD, et al. Solution structure of Vps27 UIM-ubiquitin complex important for endosomal sorting and receptor downregulation [J]. EMBO J, 2003, 22(18): 4597–4606.
[33] Sloper-Mould KE, Jemc J, Pickart CM. Distinct functional surface regions on ubiquitin [J]. J Biol Chem, 2001, 276(32): 30483–30489.
[34] Phillips CL, Thrower J, Pickart CM, et al. Structure of a new crystal form of tetraubiquitin [J]. Acta Crystallogr D Biol Crystallogr, 2001,57(part 2): 341–344.
[35] Ulrich HD. Degradation or maintenance: actions of the ubiquitin system oneukaryotic chromatin [J]. Eukaryot Cell, 2002, 1(1): 1–10.
[36] Spence J, Gali RR, Dittmar G, et al. Cell cycle-regulated modification of the ribosome by a variant multiubiquitin chain [J]. Cell, 2000, 102(1): 67–76.
[37] Koegl M, Hoppe T, Schlenker S, et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly [J]. Cell, 1999, 96(5): 635–644.
[38] Lindsten K, de Vrij FM, Verhoef LG, et al. Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion protein degradation substrate that blocks proteasomal degradation [J]. J Cell Biol, 2002,157(3): 417–427
[39]Saeki Y, Tayama Y, Toh-e A, et al. Definitive evidence for Ufd2-catalyzed elongation of the ubiquitin chain through Lys48 linkage [J]. Biochem Biophys Res Commun, 2004, 320(3): 840–845.
[40] Baboshina OV, Haas AL. Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26 S proteasome subunit 5 [J]. J Biol Chem, 1996, 271(5): 2823–2831.
[41] Hofmann RM, Pickart CM. In vitro assembly and recognition of Lys-63 polyubiquitin chains [J]. J Biol Chem, 2001, 276(30): 27936–27943.
[42] Peters JM. The anaphase-promoting complex: proteolysis in mitosis and beyond [J]. Mol Cell, 2002, 9(5): 931–943.
[43] Aristarkhov A. Eytan E, Moghe A, et al. E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins [J]. Proc. Natl Acad. Sci. USA,1996, 93(9): 4294–4299
[44]Yu H, King RW, Peters JM, et al. Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation [J]. Curr Biol, 1996, 6(4): 455–466 .
[45]Townsley FM, Aristarkhov A, Beck S, et al. Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase [J]. Proc. Natl Acad. Sci USA, 1997, 94(6): 2362–2367
[46] Seino H, Kishi T, Nishitani H, et al. Two ubiquitin-conjugating enzymes, UbcP1/Ubc4 and UbcP4/Ubc11, have distinct functions for ubiquitination of mitotic cyclin [J]. Mol Cell Biol, 2003, 23(10): 3497–3505.
[47] Mathe E, Kraft C, Giet R, et al. The E2-C vihar is required for the correct spatiotemporal proteolysis of cyclin B and itself undergoes cyclical degradation [J]. Curr Biol, 2004, 14(19): 1723–1733
[48] Townsley FM, Ruderman JV. Functional analysis of the Saccharomyces cerevisiae UBC11 gene [J].Yeast, 1998, 14(8): 747–757
[49] Carroll CW, Morgan DO. The Doc1 subunit is a processivity factor for the anaphase-promoting complex [J]. Nature Cell Biol, 2002, 4(11): 880–887
[50] Schwab M, Neutzner M, MockerD, et al. Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC [J]. EMBO J, 2001, 20(18): 5165–5175
[51] Passmore LA, McCormack EA, Au SW, et al. Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition [J].EMBO J, 2003, 22(4): 786–796
[52] Vodermaier HC, Gieffers C, Maurer-Stroh S, et al.. TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1 [J]. Curr Biol, 2003, 13(17): 1459–1468
[53] Kraft C, Vodermaier HC, Maurer-Stroh S, et al. The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates [J]. Mol. Cell, 2005, 18(5): 543–553
[54] Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway [J]. Nature, 1991, 349(6305): 132–138
[55] Pfleger CM, Kirschner MW. The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1 [J]. Genes Dev, 2000, 14(6): 655–665.
[56] Clute P, Pines J. Temporal and spatial control of cyclin B1 destruction in metaphase [J]. Nature Cell Biol, 1999, 1(2): 82–87
[57] Murray AW, Solomon MJ, Kirschner MW. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity [J]. Nature,1989, 339(6222): 280–286
[58] King RW, Glotzer M, Kirschner MW. Mutagenic analysis of the destructionsignal of mitotic cyclins and structural characterization of ubiquitinated intermediates [J]. Mol. Biol. Cell, 1996, 7(9): 1343–1357
[59] Jeffrey PD, Russo AA, Polyak K, et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex [J]. Nature, 1995, 376(6538): 313–320
[60] Diffley JF. Regulation of early events in chromosome replication [J]. Curr. Biol, 2004, 14(18) R778–R786
[61] McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis [J]. Cell, 1998, 93(6): 1043–1053
[62] Wohlschlegel JA , Dwyer BT, Dhar SK, et al. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1 [J]. Science, 2000, 290(5500): 2309–2312
[63]Tada S, Li A, Maiorano D, et al. Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin [J]. Nature Cell Biol, 2001, 3(2): 107–113
[64] Quinn LM, Herr A, McGarry TJ, et al.The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis [J]. Genes Dev, 2001, 15(20): 2741–2754
[65] Nasmyth K. Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis [J]. Annu. Rev. Genet, 2001, 35: 673–745
[66] Yamamoto A, Guacci V, Koshland D. Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae [J]. J Cell Biol, 1996, 133(1): 85–97
[67] Jallepalli PV, Waizenegger IC, Bunz F, et al. Securin is required for chromosomal stability in human cells [J]. Cell, 2001, 105(4): 445–457
[68] Mei J, Huang X, Zhang P. Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts [J]. Cur Biol, 2001, 11(15): 1197–1201
[69] Wang Z, Yu R, Melmed S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia,aberrant cell cycle progression, and premature centromere division [J]. Mol. Endocrinol, 2001, 15(11): 1870–1879
[70] Stemmann O, Zou H, Gerber SA, et al. Dual inhibition of sister chromatid separation at metaphase [J]. Cell, 2001, 107(6): 715–726
[71] Gorr IH, Boos D, Stemmann O. Mutual inhibition of separase and Cdk1 by two-step complex formation [J]. Mol Cell, 2005,19(1): 135–141
[72] Shteinberg M, Protopopov Y, Listovsky T, et al. A. Phosphorylation of the cyclosome is required for its stimulation by Fizzy/Cdc20 [J]. Biochem. Biophys. Res Commun, 1999, 260(1): 193–198
[73] Kramer ER, Scheuringer N, Podtelejnikov AV, et al. Mitotic regulation of the APC activator proteins CDC20 and CDH1 [J]. Mol Biol Cell, 2000, 11(5): 1555–1569
[74] Rudner AD, Murray AW. Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex [J]. J. Cell Biol, 2000, 149(7): 1377–1390
[75] Golan A, Yudkovsky Y, Hershko A. The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1–cyclin B and Plk [J]. J Biol Chem, 2002, 2779(18): 15552–15557
[76] Kraft C, Herzog F, Gieffers C, et al. Mitotic regulation of the human anaphase-promoting complex by phosphorylation [J]. EMBO J, 2003, 22(24): 6598–6609
[77] Zachariae W, Schwab M, Nasmyth K, et al. Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex [J]. Science, 1998, 282(5394): 1721–1724
[78] Jaspersen SL, Charles JF, Morgan DO. Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14 [J]. Curr Biol, 1999, 9(5): 227–236
[79] Blanco MA, Sanchez-Diaz A, de Prada JM, et al. APCSte9/Srw1 promotes degradation of mitotic cyclins in G1 and is inhibited by Cdc2 phosphorylation [J]. EMBO J, 2000, 19(15): 3945–3955
[80] Yamaguchi S, Okayama H, Nurse P. Fission yeast Fizzy-related protein Srw1p is a G1-specific promoter of mitotic cyclin B degradation [J]. EMBO J, 2000, 19(15): 3968–3977
[81] Visintin R, Craig K, Hwang ES, et al. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation [J].Mol. Cell, 1998, 2(6): 709–718
[82] Hagting A, Den Elzen N, Vodermaier HC, et al. Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1 [J].J. Cell Biol, 2002, 157(7): 1125–1137
[83] Prinz S, Hwang ES, Visintin R, et al. The regulation of Cdc20 proteolysis reveals a role for APC components Cdc23 and Cdc27 during S phase and early mitosis [J]. Curr Biol, 1998, 8(13): 750–760
[84] Shirayama M, Zachariae W, Ciosk R, et al. The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/Fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae [J].EMBO J, 1998, 17(5):1336–1349
[85] Sorensen CS, Lukas C, Kramer ER, et al. Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis [J]. Mol Cell Biol, 2000, 20(20): 7613–7623
[86] Huang JN, Park I, Ellingson E, et al. Activity of the APCCdh1 form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p [J].J Cell Biol, 2001, 154(1): 85–94
[87] Knoblich JA, Sauer K, Jones L, et al. Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation [J]. Cell, 1994, 77(1): 107–120
[88] Dong X, Zavitz KH, Thomas BJ, et al. Control of G1 in the developing Drosophila eye: Rca1 regulates Cyclin A [J]. Genes Dev, 1997, 11(1): 94–105
[89] Grosskortenhaus R, Sprenger F. Rca1 inhibits APC–Cdh1Fzr and is required to prevent cyclin degradation in G2 [J].Dev. Cell, 2002, 2: 29–40
[90] Lukas C, S?rensen CS, Kramer E, et al. Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex [J].Nature, 1999, 401(6755): 815–818
[91] Hsu JY, Reimann JD, Sorensen CS, et al.E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1 [J]. Nature Cell Biol, 2002, 4(5): 358–366
[92] Reimann JD, Gardner BE, Margottin-Goguet F, et al. Emi1 regulates the anaphase-promoting complex by a different mechanism than Mad2 proteins [J]. Genes Dev, 2001, 15(24): 3278–3285
[93] Rape M, Kirschner MW. Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry [J]. Nature, 2004, 432(7017): 588–595
[94] Yamanaka A, Hatakeyama S, Kominami K, et al. Cell cycle-dependent expression of mammalian E2-C regulated by the anaphase-promoting complex/cyclosome [J]. Mol Biol Cell, 2000, 11(8): 2821–2831
[95] Benmaamar R, Pagano M. Involvement of the SCF complex in the control of Cdh1 degradation in S-phase [J]. Cell Cycle, 2005, 4(9): 1230–1232
[96] Elzen den N, Pines J. Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase [J]. J Cell Biol, 2001, 153(1): 121–136
[97] Geley S, Kramer E, Gieffers C, et al. Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint [J].J. Cell Biol, 2001, 153(1): 137–148
[98] Hames RS, Wattam SL, Yamano H, et al. APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box [J].EMBO J, 2001, 20(24): 7117–7127
[99] Rieder CL, Schultz A, Cole R, et al. Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle [J]. J Cell Biol, 1994, 127(5): 1301–1310
[100]Rieder CL, Cole RW, Khodjakov A, et al. The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores [J]. J. Cell Biol, 1995, 130(4): 941–948
[101]Musacchio A, Hardwick KG. The spindle checkpoint: structural insightsinto dynamic signalling [J]. Nature Rev. Mol. Cell Biol, 2002, 3(10) 731–741
[102]Li Y, Gorbea C, Mahaffey D, et al. MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity [J]. Proc. Natl Acad. Sci. USA, 1997, 94(23): 12431–12436
[103]Fang G, Yu H, Kirschner MW. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation [J]. Genes Dev, 1998, 12(12): 1871–1883
[104]Hwang LH, Lau LF, Smith DL, et al. Budding yeast Cdc20: a target of the spindle checkpoint [J]. Science, 1998, 279(5335): 1041–1044
[105]Kim SH, Lin DP, Matsumoto S, et al. Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint [J]. Science, 1998, 279(5353): 1045–1047
[106]Sudakin V, Chan GK, Yen TJ. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2 [J]. J. Cell Biol, 2001, 154(5): 925–936
[107]Tang Z, Bharadwaj R, Li B, et al. Mad2-independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1 [J]. Dev Cell, 2001,1(2): 227–237
[108]Fang G. Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex [J]. Mol. Biol. Cell, 2002, 13(3): 755–766
[109]Sironi L, Melixetian M, Faretta M, et al. Mad2 binding to Mad1 and Cdc20, rather than oligomerization, is required for the spindle checkpoint [J]. EMBO J, 2001, 20(22): 6371–6382
[110]Luo X, Tang Z, Rizo J, et al. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20 [J]. Mol. Cell, 2002, 9(1): 59–71
[111]Sironi L , Mapelli M, Knapp S, et al. Crystal structure of the tetrameric Mad1–Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint [J]. EMBO J, 2002, 21(10): 2496–2506
[112]Shah JV , Botvinick E, Bonday Z, et al. Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing [J]. CurrBiol, 2004 14(11): 942–952
[113]De Antoni, Pearson CG, Cimini D, et al. The Mad1–Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint [J]. Curr Biol, 2005, 15(3): 214–225
[114]Fraschini R , Beretta A, Sironi L, et al. Bub3 interaction with Mad2, Mad3 and Cdc20 is mediated by WD40 repeats and does not require intact kinetochores [J]. EMBO J, 2001, 20(23): 6648–6659
[115]Shirayama M, Toth A, Galova M, et al. APCCdc20 promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5 [J].Nature, 1999, 402(6758): 203–207
[116]Schwab M, Lutum AS, Seufert W. Yeast Hct1 is a regulator of Clb2 cyclin proteolysis [J]. Cell, 1997, 90(4): 683–693
[117]Visintin R, Prinz S, Amon A. CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis [J].Science, 1997, 278(5337): 460–463
[118]Rape M, Reddy SK, Kirschner MW. The processivity of multiubiquitination by the APC determines the order of substrate degradation [J]. Cell, 2006, 124(1): 89–103
[119]Hayes MJ, Kimata Y, Wattam SL, et al. Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C [J]. Nature Cell Biol, 2006, 8(6): 607–614
[120]Kallio M, Weinstein J, Daum JR, et al. Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events [J]. J. Cell Biol, 1998, 141(6): 1393–1406
[121]Wassmann K, Benezra R. Mad2 transiently associates with an APC–p55Cdc complex during mitosis [J]. Proc. Natl Acad. Sci. USA, 1998, 95(19): 11193–11198
[122]Chan GK, Jablonski SA, Sudakin V, et al. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds thecyclosome/APC [J].J Cell Biol, 1999, 146(5): 941–954
[123]Morrow CJ, Tighe A, Johnson VL, et al. Bub1 and Aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20 [J]. J Cell Sci, 2005, 118(16): 3639–3652
[124]Pickart CM, Cohen RE. Proteasomes and their kin: proteases in the machine age [J]. Na. Rev Mol Cell Biol, 2004, 5(3): 177–187.
[1]Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms [J]. Biochim Biophys Acta, 2004, 1695(1-3): 55-72.
[2]Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular signals [J]. EMBO Rep, 2008, 9(6): 536-542.
[3]Peng J, Schwartz D, Elias JE, et al. A proteomics approach to understanding protein ubiquitination [J]. Nature Biotechnol, 2003, 21(8): 921-926.
[4]Pickart CM, Fushman D. Polyubiquitin chains: polymeric protein signals [J]. Curr Opin Chem Biol, 2004, 8(6): 610–616.
[5]Visintin R, Prinz S, Amon A. CDC20 and CDH1: a family of substrate specific activators of APC-dependent proteolysis [J]. Science, 1997, 278(5337): 460-463.
[6]Rape M, Reddy SK, Kirschner MW. The processivity of multiubiquitination by the APC determines the order of substrate degradation [J]. Cell, 2006, 124(1): 89-103.
[7]Hochstrasser M. Lingering mysteries of ubiquitin-chain assembly [J]. Cell, 2006, 124(1): 27-34.
[8]Rodrigo-Brenni MC, Morgan DO. Sequential E2s drive polyubiquitin chain assembly on APC targets [J]. Cell, 2007, 130(1): 127-139.
[9]Kirkpatrick DS, Hathaway NA, Hanna J, et al. Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology [J]. Nature Cell Biol, 2006, 8(7): 700-710.
[10]Petroski MD, Deshaies RJ. Context of multiubiquitin chain attachment influences the rate of Sic1 degradation [J]. Mol. Cell, 2003, 11(6): 1435-1444.
[11]King RW, Glotzer M, Kirschner MW. Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates [J]. Mol. Biol. Cell, 1996, 7(9): 1343-1357.
[12]Zou H, McGarry TJ, Bernal T, et al. Identification of a VertebrateSister-Chromatid Separation Inhibitor Involved in Transformation and Tumorigenesis [J]. Science, 1999, 285(5426): 418-422.
[13]Aristarkhov A, Eytan E, Moghe A, et al. E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins [J]. Proc. Natl. Acad. Sci. USA , 1996, 93(9): 4294-4299.
[14]Yu H, King RW, Peters JM, et al. Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation [J]. Curr Biol, 1996, 6(4): 455-466.
[15]Chen Z, Pickart CM. A 25-kilodalton ubiquitin carrier protein (E2) catalyzes multiubiquitin chain synthesis via lysine 48 of ubiquitin [J]. J Biol Chem, 1990, 265(35): 21835-21842.
[16]Pickart CM, Vella AT. Levels of active ubiquitin carrier proteins decline during Erythroid maturation [J]. J Biol Chem, 1988, 263(24): 12028-12035.
[17]Liu Z, Diaz LA, Haas AL, et al. cDNA cloning of a novel human ubiquitin carrier protein. An antigenic domain specifically recognized by endemic pemphigus foliaceus autoantibodies is encoded in a secondary reading frame of this human epidermal transcript [J]. J Biol Chem, 1992, 267(22): 15829-15835.
[18]Baboshina OV, Haas AL. Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26 S proteasome subunit 5 [J]. J Biol Chem, 1996, 271(5): 2823-2831.
[19]Tedesco D, Zhang J, Trinh L, et al. The ubiquitin-conjugating enzyme E2-EPF is overexpressed in primary breast cancer and modulates sensitivity to topoisomerase II inhibition [J]. Neoplasia, 2007, 9(7): 601-613.
[20]Braunstein I, Miniowitz S, Moshe Y, et al. Inhibitory factors associated with anaphase-promoting complex/cylosome in mitotic checkpoint [J]. Proc Natl Acad Sci, 2007, 104(12): 4870-4875.
[21]Reddy SK, Rape M, Kirschner MW. Ubiquitination by the anaphasepromoting complex drives spindle checkpoint inactivation [J]. Nature, 2007, 446(7138): 921-925.
[22]Summers MK, Pan B, Mukhyala K, et al. The unique N terminus of the UbcH10 E2 enzyme controls the threshold for APC activation and enhances checkpoint regulation of the APC [J]. Mol Cell, 2008, 31(4): 544-556.
[23]Alexandru G., Graumann J, Smith GT, et al. UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover [J]. Cell, 2008, 134(5): 804-816.
[24]Bennett EJ, Shaler TA, Woodman B, et al. Global changes to the ubiquitin system in Huntington's disease [J]. Nature, 2007, 448(7154): 704–708.
[25]Thrower JS, Hoffman L, Rechsteiner M, et al. Recognition of the polyubiquitin proteolytic signal [J]. EMBO J, 2000, 19(1): 94-102.
[26]Christensen DE, Brzovic PS, Klevit RE. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages [J]. Nat. Struct. Mol. Biolm 2007, 14(10): 941-948.
[27]Windheim M, Peggie M, Cohen P. Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology [J]. Biochem J, 2008, 409(3): 723-729.
[28]Jin L, Williamson A, Banerjee S, Philipp I, Rape M. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex [J]. Cell, 2008, 133(4):653-665.