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Polymerization of proteins into amyloid protofibrils shares common critical oligomeric states but differs in the mechanisms of their formation

Item Type:Article
Title:Polymerization of proteins into amyloid protofibrils shares common critical oligomeric states but differs in the mechanisms of their formation
Creators Name:Modler, A.J. and Fabian, H. and Sokolowski, F. and Lutsch, G. and Gast, K. and Damaschun, G.
Abstract:Amyloid protofibril formation of phosphoglycerate kinase (PGK) and Syrian hamster prion protein (SHaPrP(90-232)) were investigated by static and dynamic light scattering, size exclusion chromatography and electron microscopy. Changes in secondary structure were monitored by Fourier transform infrared spectroscopy and by circular dichroism. Protofibril formation of the two proteins is found to be a two-stage process. At the beginning, an ensemble of critical oligomers is built up. These critical oligomeric states possess a predominant {beta}-sheet structure and do not interact considerably with monomers. Initial oligomerization and transition to {beta}-sheet structure are coupled events differing in their details for both proteins. Intermediate oligomeric states (dimers, trimers, etc.) are populated in case of PGK, whereas SHaPrP(90-232) behaves according to an apparent two-state reaction between monomers and octamers rich in {beta}-structure with a reaction order varying between 2 and 4. All oligomers coalesce to PGK protofibrils in the second stage, while SHaPrP(90-232) protofibrils are only formed by a subpopulation. The rates of both growth stages can be tuned in case of PGK by different salts preserving the underlying generalized diffusion-collision mechanism. The different kinetics of the early misfolding and oligomerization events of the two proteins argue against a common mechanism of protofibril formation. A classification scheme for misassembly mechanisms of proteins based on energy landscapes is presented. It includes scenarios of downhill polymerization to which protofibril formation of PGK and SHaPrP(90-232) belong.
Keywords:Amyloid, Kinetics, Misfolding, Oligomer, PGK, Prion, Protofibril, Animals
Source:Amyloid
ISSN:1350-6129
Publisher:Pathenon Publishing Group (U.S.A.)
Volume:11
Number:4
Page Range:215-231
Date:1 January 2004
Official Publication:https://doi.org/10.1080/13506120400014831
PubMed:View item in PubMed

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