尖吻蝮蛇FIX/FX-bps的抗凝血和降血压活性机理及FIX/FX亲和纯化的研究
摘要
C-型凝集素类似蛋白具有与C-型凝集素类似的结构,但没有凝集素活性。蛇毒中C-型凝集素类似蛋白具有多种生物活性,包括抗凝血和血小板调节活动。凝血因子IX/凝血因子X结合蛋白属于C-型凝集素类似蛋白,它们广泛存在于蝰科蛇毒中。它们都是通过与血液中凝血因子IX或者凝血因子X结合来抑制凝血反应,所有结合反应都依赖于Ca~(2+)等离子。尖吻蝮蛇蛇毒中抗凝血因子(IACFⅠ)和抗凝血因子(ACFⅡ)是凝血因子IX/X结合蛋白家族中的两个新成员。本论文主要研究金属离子对ACFⅠ和ACFⅡ的结构稳定性和功能的影响、ACFⅠ和ACFⅡ对血液循环系统的影响以及它们在亲和纯化凝血因子IX和凝血因子X方面的应用。全文分为四章。
在第一章中,我们对凝血过程分子机理、凝血因子IX和凝血因子X等重要凝血因子的性质和功能、凝血因子IX和凝血因子X纯化技术、C-型凝集素类似蛋白以及凝血因子IX/X结合蛋白家族等进行了综述。
在第二章中,我们研究了ACFⅠ和ACFⅡ在体内抗凝血活性、碱土金属离子与ACFⅠ和ACFⅡ的结合反应以及它们对ACFⅠ和ACFⅡ的结构稳定性和功能的影响。ACFⅠ和ACFⅡ在老鼠体内表现出显著的抗凝血活性,它们都显著延长APTT和PT,都对TT没有影响,表明它们的抗凝血作用与抑制凝血因子IX/X活性有关。非变性聚丙烯酰胺凝胶电泳和表面等离子共振的结果都显示,ACFⅡ与FX_a结合反应不是绝对依赖Ca~(2+),Mg~(2+)、Sr~(2+)和Ba~(2+)也可以诱导ACFⅡ与FX_a结合反应。与ACFⅡ结合的金属离子半径不仅显著影响金属离子与ACF II结合亲和性,而且也显著影响ACFⅡ抗GdnHCl变性和热变性的结构稳定性。而与凝血因子X结合的金属离子半径显著影响ACFⅡ与FX结合亲和性。金属离子对ACFⅡ亲和性强弱和金属离子诱导ACFⅡ结构稳定性能力大小遵循相同顺序:Ca~(2+) > Sr~(2+) > Ba~(2+)。而金属离子诱导的ACFⅡ与FX结合反应的能力大小为:Mg~(2+) > Ca~(2+) > Sr~(2+) > Ba~(2+)。虽然Mg~(2+)对ACFⅡ的亲和性最低,但Mg~(2+)诱导ACFⅡ与FX结合反应能力最强。我们的实验结果表明,金属离子与ACFⅡ结合能显著增强ACFⅡ结构稳定性,但金属离子与ACFⅡ的结合反应不是ACFⅡ与FX_a发生结合反应的前提条件;金属离子与FX_a结合反应才是ACFⅡ与FX_a相互识别的前提条件。另外,ACFⅡ是基于金属离子半径选择结合Ca~(2+)。
在第三章中,我们利用凝血因子IX/X结合蛋白作为亲和配基,建立了快速高效亲和纯化凝血因子IX和凝血因子X的方法。新配基结合凝血因子IX及凝血因子X的亲和能力强,而且在温和的条件下就可以方便的洗脱下来凝血因子IX和凝血因子X。通过凝血因子IX/X结合蛋白亲和柱层析,可以直接从任何血浆中分离出仅含有凝血因子IX和凝血因子X的混合物。再经过FPLC共两步色谱就可同时得到高纯度的凝血因子IX和凝血因子X。该方法纯化效率和产率与单克隆抗体亲和层析方法相当。单克隆抗体的制备方法繁琐,抗体价格昂贵,而抗体不稳定。而新配基凝血因子IX/X结合蛋白是天然配基,长期稳定,价格便宜,很方便大规模工业制备。另外,用单克隆抗体亲和层析只能从一个特定动物血浆中纯化一种凝血因子,而用新亲和层析方法可以从任何血浆和溶液中同时纯化出凝血因子IX和凝血因子X。因此新亲和层析方法可用来工业上大规模纯化凝血因子IX和凝血因子X,以便为B型血友病患者和提供高纯而廉价的凝血因子IX。
在第四章中,我们研究了ACFⅠ和ACFⅡ对大鼠血液循环系统的影响,发现ACFⅡ具有显著的降血压活性,同时对心率没有产生显著的影响。静脉注射ACFⅡ能迅速导致大鼠血压显著下降并在几十秒后达到最大下降幅度,接着血压缓慢升高,恢复到明显低于给药前水平的平台值,并长期维持这个较低血压的平台状态。在体外,ACFⅡ能诱导血管舒张。血管内皮细胞中有一氧化氮(NO)合成酶,该酶合成NO。NO是信号分子,它能诱导血管平滑肌舒张。N-硝基精氨酸甲酯(L-NAME)是NO合成酶抑制剂。在体外,L-NAME能显著抑制ACFⅡ的舒张血管活性;在体内,L-NAME能显著抑制ACFⅡ的降血压活性。由此可知,ACFⅡ通过NO信号途径诱导血管舒张从而导致血压下降。因此ACFⅡ是凝血因子IX/X结合蛋白家族中一个独特的多功能蛋白,它通过不同途径作用与血液系统,兼具抗凝血和降血压双重活性。尽管ACFⅠ和ACFⅡ具有十分相似的空间结构,但ACFⅠ没有任何降压活性。
C-type lectin-like proteins (CLPs) have similar structures to that of C-type lectins, but they have no lectin activity. The CLPs from snake venom have a variety of biological activities, including anticoagulant- and platelet-modulating activities. A family of coagulation factor IX/factor X-binding protein (IX/X-bp) which belongs to CLPs has been identified from the venoms of different snake species. IX/X-bps interact with theγ-carboxyglutamic acid (Gla) domain of factor IX/IX_a and/or factor X/X_a in a Ca~(2+)-dependent manner and thereby block the amplification of the coagulation cascade. Anticoagulation factor I (ACFⅠ) and anticoagulation factor II (ACFⅡ) purified from the venom of Agkistrodon acutus are two members of the IX/X-bp protein family. In this thesis, the effects of metal ions on the structural stability and function of ACFⅠand ACFⅡ, the hypotensive effects of ACFⅠand ACF II on the cardiovascular system, and their application in the purification of coagulation factor IX and coagulation factor X have been investigated. The whole thesis is divided into four chapters.
The first chapter gives a brief overview of the molecular mechanism of coagulation process, the character and function of the important coagulation factors, especially on coagulation factor IX and coagulation factor X, the purification technology of coagulation factor IX/X, C-type lectin-like proteins, and coagulation factor IX/X-binding protein family.
In the second chapter, the anticoagulant activity of ACFⅠand in vivo, the thermodynamics of the binding of alkaline earth metal ions to ACFⅡand their effects on the stability of ACFⅡand the binding of ACFⅡto FX_a were investigated by isothermal titration calorimetry, fluorescence, differential scanning calorimetry and surface plasmon resonance, respectively. Both ACFⅠand ACFⅡexhibit high anticoagulation activity in vivo. The binding of ACFⅡto FX_a does not have an absolute requirement for Ca~(2+). Mg~(2+), Sr~(2+) and Ba~(2+) can induce the binding of ACFⅡto FX_a. The radii of the cations bound in ACFⅡcrucially affect the binding affinity of ACFⅡto cations and the structural stability of ACFⅡagainst GdnHCl and thermal denaturation, while the radii of cations bound in FX_a markedly affect on the binding affinity between ACFⅡand FX_a. The binding affinities of ACFⅡfor cations and the capacities of metal-induced stabilization of ACFⅡfollow the same trend Ca~(2+) > Sr~(2+) > Ba~(2+). The metal-induced binding affinities of ACFⅡto FX_a follow the trend Mg~(2+) > Ca~(2+) > Sr~(2+) > Ba~(2+). Although Mg~(2+) shows significantly low binding affinity with ACFⅡ, Mg~(2+) is the most effective to induce the binding of ACFⅡwith FX_a. Our observations suggest that in blood, the bindings of Ca~(2+) in two sites of ACFⅡincrease the structural stability of ACFⅡ, but these bindings are not essential for the binding of ACFⅡwith FX_a, and that the binding of Mg~(2+) and Ca~(2+) to FX_a may be essential for the recognition between FX_a and ACFⅡ. Like Ca~(2+), the abundant Mg~(2+) in blood also plays an important role in the anticoagulation of ACFⅡ.
In the third chapter, we have developed an rapid affinity chromatography procedure using coagulation factor IX/factor X-binding proteins as novel affinity ligands to isolate coagulation factor IX and coagulation factor X from plasma. The native affinity ligands efficiently bind FIX/FX and release them under very mild conditions. FIX and FX can be simultaneously purified from unclarified plasma by IX/X-bps affinity chromatography followed by HPLC with a purification factor and yield similar to that of monoclonal antibody immunoaffinity chromatography. In contrast to monoclonal antibody that is cumbersome, expensive and suffer from its instability, the novel affinity ligands IX/X-bps are long-term stable and cheap to prepare in large scale. In addition, monoclonal antibody immunoaffinity chromatography is used to purify FIX only from the specific plasma, while the new affinity chromatography can be used to purify both FIX and FX from any unclarified plasma or solutions. This new affinity chromatography has potential application for the industrial scale purification of FIX and FX for specific replacement therapy in hemophilia B and patients with FX deficiency.
In the fourth chapter, the effects of ACFⅠand ACFⅡon the mean arterial blood pressure (MABP) and heart rate (HR) in anesthetized rats have been investigated. The results indicate that ACFⅡinduces a dose-dependent response in rats with a short fast drop of MABP followed by an increase and then a longer lasting slight decrease in MABP, but does not obviously affect HR. ACFⅡ-induced hypotension is significantly blocked by the NO synthase inhibitor N-omega-L-arginine methyl ester (L-NAME). ACFⅡproduces a concentration-dependent relaxation of rat aortic rings with functional-endothelium. The ACFⅡ-induced vasodilatation is completely inhibited by removal of endothelium and significantly inhibited by pretreatment with L-NAME. These observations demonstrate that ACFⅡinduces hypotension through an endothelium-dependent vasodilation, which is strongly mediated by the release of NO from endothelium. Therefore, ACFⅡis so far identified as the first unique bifunctional protein in the IX/X-bp family that has both anticoagulant and hypotensive effects on the blood of rats through different pathways. However, ACFⅠdoes not show any hypotensive effect in rats.
在第一章中,我们对凝血过程分子机理、凝血因子IX和凝血因子X等重要凝血因子的性质和功能、凝血因子IX和凝血因子X纯化技术、C-型凝集素类似蛋白以及凝血因子IX/X结合蛋白家族等进行了综述。
在第二章中,我们研究了ACFⅠ和ACFⅡ在体内抗凝血活性、碱土金属离子与ACFⅠ和ACFⅡ的结合反应以及它们对ACFⅠ和ACFⅡ的结构稳定性和功能的影响。ACFⅠ和ACFⅡ在老鼠体内表现出显著的抗凝血活性,它们都显著延长APTT和PT,都对TT没有影响,表明它们的抗凝血作用与抑制凝血因子IX/X活性有关。非变性聚丙烯酰胺凝胶电泳和表面等离子共振的结果都显示,ACFⅡ与FX_a结合反应不是绝对依赖Ca~(2+),Mg~(2+)、Sr~(2+)和Ba~(2+)也可以诱导ACFⅡ与FX_a结合反应。与ACFⅡ结合的金属离子半径不仅显著影响金属离子与ACF II结合亲和性,而且也显著影响ACFⅡ抗GdnHCl变性和热变性的结构稳定性。而与凝血因子X结合的金属离子半径显著影响ACFⅡ与FX结合亲和性。金属离子对ACFⅡ亲和性强弱和金属离子诱导ACFⅡ结构稳定性能力大小遵循相同顺序:Ca~(2+) > Sr~(2+) > Ba~(2+)。而金属离子诱导的ACFⅡ与FX结合反应的能力大小为:Mg~(2+) > Ca~(2+) > Sr~(2+) > Ba~(2+)。虽然Mg~(2+)对ACFⅡ的亲和性最低,但Mg~(2+)诱导ACFⅡ与FX结合反应能力最强。我们的实验结果表明,金属离子与ACFⅡ结合能显著增强ACFⅡ结构稳定性,但金属离子与ACFⅡ的结合反应不是ACFⅡ与FX_a发生结合反应的前提条件;金属离子与FX_a结合反应才是ACFⅡ与FX_a相互识别的前提条件。另外,ACFⅡ是基于金属离子半径选择结合Ca~(2+)。
在第三章中,我们利用凝血因子IX/X结合蛋白作为亲和配基,建立了快速高效亲和纯化凝血因子IX和凝血因子X的方法。新配基结合凝血因子IX及凝血因子X的亲和能力强,而且在温和的条件下就可以方便的洗脱下来凝血因子IX和凝血因子X。通过凝血因子IX/X结合蛋白亲和柱层析,可以直接从任何血浆中分离出仅含有凝血因子IX和凝血因子X的混合物。再经过FPLC共两步色谱就可同时得到高纯度的凝血因子IX和凝血因子X。该方法纯化效率和产率与单克隆抗体亲和层析方法相当。单克隆抗体的制备方法繁琐,抗体价格昂贵,而抗体不稳定。而新配基凝血因子IX/X结合蛋白是天然配基,长期稳定,价格便宜,很方便大规模工业制备。另外,用单克隆抗体亲和层析只能从一个特定动物血浆中纯化一种凝血因子,而用新亲和层析方法可以从任何血浆和溶液中同时纯化出凝血因子IX和凝血因子X。因此新亲和层析方法可用来工业上大规模纯化凝血因子IX和凝血因子X,以便为B型血友病患者和提供高纯而廉价的凝血因子IX。
在第四章中,我们研究了ACFⅠ和ACFⅡ对大鼠血液循环系统的影响,发现ACFⅡ具有显著的降血压活性,同时对心率没有产生显著的影响。静脉注射ACFⅡ能迅速导致大鼠血压显著下降并在几十秒后达到最大下降幅度,接着血压缓慢升高,恢复到明显低于给药前水平的平台值,并长期维持这个较低血压的平台状态。在体外,ACFⅡ能诱导血管舒张。血管内皮细胞中有一氧化氮(NO)合成酶,该酶合成NO。NO是信号分子,它能诱导血管平滑肌舒张。N-硝基精氨酸甲酯(L-NAME)是NO合成酶抑制剂。在体外,L-NAME能显著抑制ACFⅡ的舒张血管活性;在体内,L-NAME能显著抑制ACFⅡ的降血压活性。由此可知,ACFⅡ通过NO信号途径诱导血管舒张从而导致血压下降。因此ACFⅡ是凝血因子IX/X结合蛋白家族中一个独特的多功能蛋白,它通过不同途径作用与血液系统,兼具抗凝血和降血压双重活性。尽管ACFⅠ和ACFⅡ具有十分相似的空间结构,但ACFⅠ没有任何降压活性。
C-type lectin-like proteins (CLPs) have similar structures to that of C-type lectins, but they have no lectin activity. The CLPs from snake venom have a variety of biological activities, including anticoagulant- and platelet-modulating activities. A family of coagulation factor IX/factor X-binding protein (IX/X-bp) which belongs to CLPs has been identified from the venoms of different snake species. IX/X-bps interact with theγ-carboxyglutamic acid (Gla) domain of factor IX/IX_a and/or factor X/X_a in a Ca~(2+)-dependent manner and thereby block the amplification of the coagulation cascade. Anticoagulation factor I (ACFⅠ) and anticoagulation factor II (ACFⅡ) purified from the venom of Agkistrodon acutus are two members of the IX/X-bp protein family. In this thesis, the effects of metal ions on the structural stability and function of ACFⅠand ACFⅡ, the hypotensive effects of ACFⅠand ACF II on the cardiovascular system, and their application in the purification of coagulation factor IX and coagulation factor X have been investigated. The whole thesis is divided into four chapters.
The first chapter gives a brief overview of the molecular mechanism of coagulation process, the character and function of the important coagulation factors, especially on coagulation factor IX and coagulation factor X, the purification technology of coagulation factor IX/X, C-type lectin-like proteins, and coagulation factor IX/X-binding protein family.
In the second chapter, the anticoagulant activity of ACFⅠand in vivo, the thermodynamics of the binding of alkaline earth metal ions to ACFⅡand their effects on the stability of ACFⅡand the binding of ACFⅡto FX_a were investigated by isothermal titration calorimetry, fluorescence, differential scanning calorimetry and surface plasmon resonance, respectively. Both ACFⅠand ACFⅡexhibit high anticoagulation activity in vivo. The binding of ACFⅡto FX_a does not have an absolute requirement for Ca~(2+). Mg~(2+), Sr~(2+) and Ba~(2+) can induce the binding of ACFⅡto FX_a. The radii of the cations bound in ACFⅡcrucially affect the binding affinity of ACFⅡto cations and the structural stability of ACFⅡagainst GdnHCl and thermal denaturation, while the radii of cations bound in FX_a markedly affect on the binding affinity between ACFⅡand FX_a. The binding affinities of ACFⅡfor cations and the capacities of metal-induced stabilization of ACFⅡfollow the same trend Ca~(2+) > Sr~(2+) > Ba~(2+). The metal-induced binding affinities of ACFⅡto FX_a follow the trend Mg~(2+) > Ca~(2+) > Sr~(2+) > Ba~(2+). Although Mg~(2+) shows significantly low binding affinity with ACFⅡ, Mg~(2+) is the most effective to induce the binding of ACFⅡwith FX_a. Our observations suggest that in blood, the bindings of Ca~(2+) in two sites of ACFⅡincrease the structural stability of ACFⅡ, but these bindings are not essential for the binding of ACFⅡwith FX_a, and that the binding of Mg~(2+) and Ca~(2+) to FX_a may be essential for the recognition between FX_a and ACFⅡ. Like Ca~(2+), the abundant Mg~(2+) in blood also plays an important role in the anticoagulation of ACFⅡ.
In the third chapter, we have developed an rapid affinity chromatography procedure using coagulation factor IX/factor X-binding proteins as novel affinity ligands to isolate coagulation factor IX and coagulation factor X from plasma. The native affinity ligands efficiently bind FIX/FX and release them under very mild conditions. FIX and FX can be simultaneously purified from unclarified plasma by IX/X-bps affinity chromatography followed by HPLC with a purification factor and yield similar to that of monoclonal antibody immunoaffinity chromatography. In contrast to monoclonal antibody that is cumbersome, expensive and suffer from its instability, the novel affinity ligands IX/X-bps are long-term stable and cheap to prepare in large scale. In addition, monoclonal antibody immunoaffinity chromatography is used to purify FIX only from the specific plasma, while the new affinity chromatography can be used to purify both FIX and FX from any unclarified plasma or solutions. This new affinity chromatography has potential application for the industrial scale purification of FIX and FX for specific replacement therapy in hemophilia B and patients with FX deficiency.
In the fourth chapter, the effects of ACFⅠand ACFⅡon the mean arterial blood pressure (MABP) and heart rate (HR) in anesthetized rats have been investigated. The results indicate that ACFⅡinduces a dose-dependent response in rats with a short fast drop of MABP followed by an increase and then a longer lasting slight decrease in MABP, but does not obviously affect HR. ACFⅡ-induced hypotension is significantly blocked by the NO synthase inhibitor N-omega-L-arginine methyl ester (L-NAME). ACFⅡproduces a concentration-dependent relaxation of rat aortic rings with functional-endothelium. The ACFⅡ-induced vasodilatation is completely inhibited by removal of endothelium and significantly inhibited by pretreatment with L-NAME. These observations demonstrate that ACFⅡinduces hypotension through an endothelium-dependent vasodilation, which is strongly mediated by the release of NO from endothelium. Therefore, ACFⅡis so far identified as the first unique bifunctional protein in the IX/X-bp family that has both anticoagulant and hypotensive effects on the blood of rats through different pathways. However, ACFⅠdoes not show any hypotensive effect in rats.
引文
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