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Delineating the Role of Helical Intermediates in Natively Unfolded Polypeptide Amyloid Assembly and Cytotoxicity
Author(s) -
De Carufel Carole Anne,
Quittot Noé,
Nguyen Phuong Trang,
Bourgault Steve
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201507092
Subject(s) - chemistry , amyloid (mycology) , cytotoxicity , biophysics , protein folding , biochemistry , microbiology and biotechnology , in vitro , biology , inorganic chemistry
Amyloid deposition is a hallmark of many diseases, such as the Alzheimer’s disease. Numerous amyloidogenic proteins, including the islet amyloid polypeptide (IAPP) associated with type II diabetes, are natively unfolded and need to undergo conformational rearrangements allowing the formation of locally ordered structure(s) to initiate self‐assembly. Recent studies have indicated that the formation of α‐helical intermediates accelerates fibrillization, suggesting that these species are on‐pathway to amyloid assembly. By identifying an IAPP derivative with a restricted conformational ensemble that co‐assembles with IAPP, we observed that helical species were off‐pathway in homogenous environment and in presence of lipid bilayers or glycosaminoglycans. Moreover, preventing helical folding potentiated membrane perturbation and IAPP cytotoxicity, indicating that stabilization of helical motif(s) is a promising strategy to prevent cell degeneration associated with amyloidogenesis.