使用D-氨基酸替代类似物研究β-淀粉样蛋白（1-42）的构象转变

Study of the conformational transition of A beta(1-42) using D-amino acid replacement analogues.

作者信息

Janek K, Rothemund S, Gast K, Beyermann M, Zipper J, Fabian H, Bienert M, Krause E

机构信息

Institute of Molecular Pharmacology and Max Delbrück Center of Molecular Medicine, Berlin, Germany.

出版信息

Biochemistry. 2001 May 8;40(18):5457-63. doi: 10.1021/bi002005e.

DOI:10.1021/bi002005e

PMID:11331010

Abstract

A critical event in Alzheimer's disease is the transition of Abeta peptides from their soluble forms into disease-associated beta-sheet-rich conformers. Structural analysis of a complete D-amino acid replacement set of Abeta(1-42) enabled us to localize in the full-length 42-mer peptide the region responsible for the conformational switch into a beta-sheet structure. Although NMR spectroscopy of trifluoroethanol-stabilized monomeric Abeta(1-42) delineated two separated helical domains, only the destabilization of helix I, comprising residues 11-24, caused a transition to a beta-sheet structure. This conformational alpha-to-beta switch was directly accompanied by an aggregation process leading to the formation of amyloid fibrils.

摘要

阿尔茨海默病中的一个关键事件是β-淀粉样肽从其可溶性形式转变为与疾病相关的富含β-折叠的构象体。对β-淀粉样蛋白（1-42）完整的D-氨基酸替代集进行结构分析，使我们能够在全长42聚体肽中定位负责转变为β-折叠结构的区域。尽管对三氟乙醇稳定的单体β-淀粉样蛋白（1-42）进行核磁共振光谱分析确定了两个分离的螺旋结构域，但只有包含11-24位残基的螺旋I的不稳定才会导致向β-折叠结构的转变。这种从α-螺旋到β-折叠的构象转变直接伴随着一个聚集过程，导致淀粉样纤维的形成。