Formation and Stabilization Model of the 42-mer A Radical: Implications for the Long-Lasting Oxidative Stress in Alzh
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- 作者：Kazuma Murakami ; Kazuhiro Irie ; Hajime Ohigashi ; Hideyuki Hara ; Masaya Nagao ; Takahiko Shimizu ; and Takuji Shirasawa
- 刊名：Journal of the American Chemical Society
- 出版年：2005
- 出版时间：November 2, 2005
- 年：2005
- 卷：127
- 期：43
- 页码：15168 - 15174
- 全文大小：455K
- 年卷期：v.127,no.43(November 2, 2005)
- ISSN：1520-5126
文摘
Amyloid fibrils mainly consist of 40-mer and 42-mer peptides (A
40, A42). A42 is believed toplay a crucial role in the pathogenesis of Alzheimer's disease because its aggregative ability and neurotoxicityare considerably greater than those of A40. The neurotoxicity of A peptides involving the generation offree radicals is closely related to the S-oxidized radical cation of Met-35. However, the cation's origin andmechanism of stabilization remain unclear. Recently, structural models of fibrillar A42 and A40 basedon systematic proline replacement have been proposed by our group [Morimoto, A.; et al. J. Biol. Chem.2004, 279, 52781] and Wetzel's group [Williams, A. D.; et al. J. Mol. Biol. 2004, 335, 833], respectively. Amajor difference between these models is that our model of A42 has a C-terminal -sheet region. Ourbiophysical study on A42 using electron spin resonance (ESR) suggests that the S-oxidized radical cationof Met-35 could be generated by the reduction of the tyrosyl radical at Tyr-10 through a turn structure atpositions 22 and 23, and stabilized by a C-terminal carboxylate anion through an intramolecular -sheet atpositions 35-37 and 40-42 to form a C-terminal core that would lead to aggregation. A time-course analysisof the generation of radicals using ESR suggests that stabilization of the radicals by aggregation might bea main reason for the long-lasting oxidative stress of A42. In contrast, the S-oxidized radical cation ofA40 is too short-lived to induce potent neurotoxicity because no such stabilization of radicals occurs inA40.
40, A42). A42 is believed toplay a crucial role in the pathogenesis of Alzheimer's disease because its aggregative ability and neurotoxicityare considerably greater than those of A40. The neurotoxicity of A peptides involving the generation offree radicals is closely related to the S-oxidized radical cation of Met-35. However, the cation's origin andmechanism of stabilization remain unclear. Recently, structural models of fibrillar A42 and A40 basedon systematic proline replacement have been proposed by our group [Morimoto, A.; et al. J. Biol. Chem.2004, 279, 52781] and Wetzel's group [Williams, A. D.; et al. J. Mol. Biol. 2004, 335, 833], respectively. Amajor difference between these models is that our model of A42 has a C-terminal -sheet region. Ourbiophysical study on A42 using electron spin resonance (ESR) suggests that the S-oxidized radical cationof Met-35 could be generated by the reduction of the tyrosyl radical at Tyr-10 through a turn structure atpositions 22 and 23, and stabilized by a C-terminal carboxylate anion through an intramolecular -sheet atpositions 35-37 and 40-42 to form a C-terminal core that would lead to aggregation. A time-course analysisof the generation of radicals using ESR suggests that stabilization of the radicals by aggregation might bea main reason for the long-lasting oxidative stress of A42. In contrast, the S-oxidized radical cation ofA40 is too short-lived to induce potent neurotoxicity because no such stabilization of radicals occurs inA40.