Copper-Binding Amyloid Precursor Protein Undergoes a Site-Specific Fragmentation in the Reduction of Hydrogen Peroxide
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- 作者：Gerd Multhaup ; Thomas Ruppert ; Andrea Schlicksupp ; Lars Hesse ; Eckhard Bill ; Rü ; diger Pipkorn ; Colin L. Masters ; and Konrad Beyreuther
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：May 19, 1998
- 年：1998
- 卷：37
- 期：20
- 页码：7224 - 7230
- 全文大小：207K
- 年卷期：v.37,no.20(May 19, 1998)
- ISSN：1520-4995
文摘
The extracellular domain of transmembrane A
amyloid precursorprotein (APP) has a Cu(II)reducing activity upon Cu(II) binding associated with theformation of a new disulfide bridge. The completeassignment of the disulfide bond revealed the involvement of cysteines144 and 158 around copper-binding histidine residues. The vulnerability of APP-Cu(I)complexes to reactive oxygen species waselaborated as a site-specific and random fragmentation of APP in atime-dependent manner and at lowconcentrations of H2O2. Analysis of thespecific reaction revealed the generation of C-terminalpolypeptides,containing the A domain. APP catalyzed the reduction ofH2O2 and oxidation of Cu(I) to Cu(II)in a"peroxidative" reaction in vitro. The resulting boundcopper-hydroxyl radical intermediate [APP-Cu(II)(·OH)] then likely participated in a Fenton typeof reaction with radical formation as a prerequisitefor protein degradation. Evidence from two observations suggeststhat the reaction takes place in twophases. Bathocuproine, a trapping agent for Cu(I), abolishedthe initial fragmentation, and chelation ofCu(II) by DTPA (diethylenetriaminepentaacetic acid) interruptedthe reaction cascade induced byH2O2at later stages. Consequently, the results suggest that acytotoxic gain-of-function of APP-Cu(I) complexesmight result in a perturbation of free radical homeostasis. Whatsignificance such a perturbation mayhave for the pathogenesis of Alzheimer's disease remains to bedetermined.
amyloid precursorprotein (APP) has a Cu(II)reducing activity upon Cu(II) binding associated with theformation of a new disulfide bridge. The completeassignment of the disulfide bond revealed the involvement of cysteines144 and 158 around copper-binding histidine residues. The vulnerability of APP-Cu(I)complexes to reactive oxygen species waselaborated as a site-specific and random fragmentation of APP in atime-dependent manner and at lowconcentrations of H2O2. Analysis of thespecific reaction revealed the generation of C-terminalpolypeptides,containing the A domain. APP catalyzed the reduction ofH2O2 and oxidation of Cu(I) to Cu(II)in a"peroxidative" reaction in vitro. The resulting boundcopper-hydroxyl radical intermediate [APP-Cu(II)(·OH)] then likely participated in a Fenton typeof reaction with radical formation as a prerequisitefor protein degradation. Evidence from two observations suggeststhat the reaction takes place in twophases. Bathocuproine, a trapping agent for Cu(I), abolishedthe initial fragmentation, and chelation ofCu(II) by DTPA (diethylenetriaminepentaacetic acid) interruptedthe reaction cascade induced byH2O2at later stages. Consequently, the results suggest that acytotoxic gain-of-function of APP-Cu(I) complexesmight result in a perturbation of free radical homeostasis. Whatsignificance such a perturbation mayhave for the pathogenesis of Alzheimer's disease remains to bedetermined.