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Oligomeric assembly of native-like precursors precedes amyloid formation by beta-2 microglobulin. Biochemistry (2004)
| Citations: | 13 - 1 self |
BibTeX
@MISC{Eakin04oligomericassembly,
author = {Catherine M. Eakin and Frank J. Attenello and Charles J. Morgan and Andrew D. Miranker},
title = {Oligomeric assembly of native-like precursors precedes amyloid formation by beta-2 microglobulin. Biochemistry},
year = {2004}
}
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Abstract
ABSTRACT: The deposition of β-2-microglobulin (β2m) as amyloid fibers results in debilitating complications for renal failure patients who are treated by hemodialysis. In vitro, wild-type β2m can be converted to amyloid under physiological conditions by exposure to biomedically relevant concentrations of Cu 2+.In this work, we have made comparative measurements of the structural and oligomeric changes in β2m at time points preceding fibrillogenesis. Our results show Cu 2+ mediates the formation of a monomeric, activated state followed by the formation of a discrete dimeric intermediate. The dimeric intermediates then assemble into tetra- and hexameric forms which display little additional oligomerization on the time scales of their own formation (<1 h). Amyloid fiber formation progresses from these intermediate states but on much longer time scales (>1 week). Although Cu 2+ is necessary for the generation and stabilization of these intermediates, it is not required for the stability of mature amyloid fibers. This suggests that Cu 2+ acts as an initiating factor of amyloidosis by inducing oligomer formation. 1 H NMR and near-UV circular dichroism are used to establish that oligomeric intermediates are native-like in structure. The native-like structure and discrete oligomeric size of β2m amyloid intermediates suggest that this protein forms fibrils by structural domain swapping. Amyloid fibers are highly ordered protein assemblies
Keyphrases
native-like precursor precedes amyloid formation beta-2 microglobulin oligomeric assembly time scale mature amyloid fiber intermediate state physiological condition oligomeric change ordered protein assembly renal failure patient near-uv circular dichroism little additional oligomerization amyloid intermediate amyloid fiber initiating factor native-like structure relevant concentration dimeric intermediate discrete dimeric intermediate discrete oligomeric size structural domain swapping amyloid fiber result oligomeric intermediate comparative measurement time point hexameric form amyloid fiber formation
