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Protein Science (2006), 15:1334-1341. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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Dichotomous versus palm-type mechanisms of lateral assembly of amyloid fibrils

Natallia Makarava, Olga V. Bocharova1, Vadim V. Salnikov2, Leonid Breydo, Maighdlin Anderson and Ilia V. Baskakov

Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA

(RECEIVED December 6, 2005; FINAL REVISION February 22, 2006; ACCEPTED March 6, 2006)

Despite possessing a common cross-beta core, amyloid fibrils are known to exhibit great variations in their morphologies. To date, the mechanism responsible for the polymorphism in amyloid fibrils is poorly understood. Here we report that two variants of mammalian full-length prion protein (PrP), hamster (Ha) and mouse (Mo) PrPs, produced morphologically distinguishable subsets of mature fibrils under identical solvent conditions. To gain insight into the origin of this morphological diversity we analyzed the early stages of polymerization. Unexpectedly, we found that despite a highly conserved amyloidogenic region (94% identity within the residues 90–230), Ha and Mo PrPs followed two distinct pathways for lateral assembly of protofibrils into mature, higher order fibrils. The protofibrils of Ha PrP first formed irregular bundles characterized by a peculiar palm-type shape, which ultimately condensed into mature fibrils. The protofibrils of Mo PrP, on the other hand, associated in pairs in a pattern resembling dichotomous coalescence. These pathways are referred to here as the palm-type and dichotomous mechanisms. Two distinct mechanisms for lateral assembly explain striking differences in morphology of mature fibrils produced from closely related Mo and Ha PrPs. Remarkable similarities between subtypes of amyloid fibrils generated from different proteins and peptides suggest that the two mechanisms of lateral assembly may not be limited to prion proteins but may be a common characteristic of polymerization of amyloidogenic proteins and peptides in general.

Keywords: conformational changes; prion; amyloid fibrils; electron microscopy; lateral assembly; protofibrils


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N. Makarava and I. V. Baskakov
The Same Primary Structure of the Prion Protein Yields Two Distinct Self-propagating States
J. Biol. Chem., June 6, 2008; 283(23): 15988 - 15996.
[Abstract] [Full Text] [PDF]


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