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Relationship between prion propensity and the rates of individual molecular steps of fibril assembly.

Wang, YQ and Buell, AK and Wang, XY and Welland, ME and Dobson, CM and Knowles, TP and Perrett, S (2011) Relationship between prion propensity and the rates of individual molecular steps of fibril assembly. J Biol Chem, 286. pp. 12101-12107.

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Abstract

Peptides and proteins possess an inherent propensity to self-assemble into generic fibrillar nanostructures known as amyloid fibrils, some of which are involved in medical conditions such as Alzheimer disease. In certain cases, such structures can self-propagate in living systems as prions and transmit characteristic traits to the host organism. The mechanisms that allow certain amyloid species but not others to function as prions are not fully understood. Much progress in understanding the prion phenomenon has been achieved through the study of prions in yeast as this system has proved to be experimentally highly tractable; but quantitative understanding of the biophysics and kinetics of the assembly process has remained challenging. Here, we explore the assembly of two closely related homologues of the Ure2p protein from Saccharomyces cerevisiae and Saccharomyces paradoxus, and by using a combination of kinetic theory with solution and biosensor assays, we are able to compare the rates of the individual microscopic steps of prion fibril assembly. We find that for these proteins the fragmentation rate is encoded in the structure of the seed fibrils, whereas the elongation rate is principally determined by the nature of the soluble precursor protein. Our results further reveal that fibrils that elongate faster but fracture less frequently can lose their ability to propagate as prions. These findings illuminate the connections between the in vitro aggregation of proteins and the in vivo proliferation of prions, and provide a framework for the quantitative understanding of the parameters governing the behavior of amyloid fibrils in normal and aberrant biological pathways.

Item Type: Article
Uncontrolled Keywords: Amino Acid Sequence Fungal Proteins Glutathione Peroxidase Microscopy, Atomic Force Microscopy, Electron Molecular Sequence Data Prions Quartz Crystal Microbalance Techniques Saccharomyces cerevisiae Proteins Sequence Homology, Amino Acid
Subjects: UNSPECIFIED
Divisions: Div B > Solid State Electronics and Nanoscale Science
Depositing User: Cron Job
Date Deposited: 07 Mar 2014 11:22
Last Modified: 17 Mar 2014 14:27
DOI: 10.1074/jbc.M110.208934

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