title: Molecular mechanisms of polypeptide aggregation in human diseases.
abstract: Protein aggregation is implicated in a plethora of neurodegenerative diseases. The proteins found to aggregate in these diseases are unrelated in their native structures and amino acid sequences, but form similar insoluble fibrils with characteristic cross-beta sheet morphologies called amyloid in the aggregated state. While both the mechanism of aggregation and the structure of the aggregates are not fully understood at the molecular level, recent studies provide strong support for the idea that protein aggregation into highly stable, insoluble amyloid structures is a general property of the polypeptide chain. For proteins with a unique native state, it is known that aggregation occurs under conditions that promote native-state destabilization in vitro and in vivo. Taken together, the results of several important recent investigations suggest three broad molecular frameworks that may underlie the conversion of normally soluble peptides and proteins into insoluble amyloid fibrils: (1) edge-strand hydrogen bonding, (2) domain-swapping, and (3) self-association of amyloidogenic fragments. We argue that these underlying scenarios are not mutually exclusive and may be protein-dependent - i.e., a protein with a high content of hinge-regions may aggregate via a runaway domain-swap, whereas a protein with a high content of amyloidogenic fragments may aggregate primarily by the self-association of these fragments. These different scenarios provide frameworks to understand the molecular mechanism of polypeptide aggregation.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Sagar D
authors.initials: SD
authors.lastname: Khare
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D003603:Cytotoxins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D011485:Protein Binding; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D000682:Amyloid; D003603:Cytotoxins; D010455:Peptides; D013482:Superoxide Dismutase