Turn Plasticity Distinguishes Different Modes of Amyloid-尾 Aggregation

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• 作者：Nasrollah Rezaei-Ghaleh ; Mehriar Amininasab ; Karin Giller ; Sathish Kumar ; Anne St眉ndl ; Anja Schneider ; Stefan Becker ; Jochen Walter ; Markus Zweckstetter
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：April 2, 2014
• 年：2014
• 卷：136
• 期：13
• 页码：4913-4919
• 全文大小：413K
• 年卷期：v.136,no.13(April 2, 2014)
• ISSN：1520-5126

文摘

Pathogenesis of Alzheimer鈥檚 disease (AD) is associated with aggregation of the amyloid-尾 (A尾) peptide into oligomeric and fibrillar assemblies; however, little is known about the molecular basis of aggregation of A尾 into distinct assembly states. Here we demonstrate that phosphorylation at serine 26 (S26) impairs A尾 fibrillization while stabilizing its monomers and nontoxic soluble assemblies of nonfibrillar morphology. NMR spectroscopy and replica-exchange molecular dynamics indicate that introduction of a phosphate group or phosphomimetic at position 26 diminishes A尾鈥檚 propensity to form a 尾-hairpin, rigidifies the region around the modification site, and interferes with formation of a fibril-specific salt bridge between aspartic acid 23 and lysine 28. The combined data demonstrate that phosphorylation of S26 prevents a distinct conformational rearrangement that is required for progression of A尾 aggregation toward fibrils and provide a basis for a possible role of phosphorylation at serine 26 in AD.