title: Delineating the Role of Helical Intermediates in Natively Unfolded Polypeptide Amyloid Assembly and Cytotoxicity.
abstract: 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.
authors.affiliation: Department of Chemistry, Université du Québec à Montréal, Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), C.P. 8888, Montréal (Canada).
authors.forename: Carole Anne
authors.initials: CA
authors.lastname: De Carufel
authors.affiliation: Department of Chemistry, Université du Québec à Montréal, Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), C.P. 8888, Montréal (Canada).
authors.forename: Noé
authors.initials: N
authors.lastname: Quittot
authors.affiliation: Department of Chemistry, Université du Québec à Montréal, Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), C.P. 8888, Montréal (Canada).
authors.forename: Phuong Trang
authors.initials: PT
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, Université du Québec à Montréal, Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), C.P. 8888, Montréal (Canada). bourgault.steve@uqam.ca.
authors.forename: Steve
authors.initials: S
authors.lastname: Bourgault
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D010455:Peptides / Q000737:chemistry*
chemical_list: D000682:Amyloid; D010455:Peptides
keywords: amyloid; glycosaminoglycans; islet amyloid polypeptide; membrane models; α-helix