Oligomeric Assembly of Native-like Precursors Precedes Amyloid Formation by β-2 Microglobulin

Authors:
Publisher website
Google Scholar
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 Cu2+. In this work, we have made comparative measurements of the structural and oligomeric changes in β2m at time points preceding fibrillogenesis. Our results show Cu2+ 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 week). Although Cu2+ is necessary for the generation and stabilization of these intermediates, it is not required for the stability of mature amyloid fibers. This suggests that Cu2+ acts as an initiating factor of amyloidosis by inducing oligomer formation. 1H 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.

This publication has 19 references indexed in Scilit: