Article abstract
Nature Structural & Molecular Biology 15, 965 - 971 (2008)
Published online: 31 August 2008 | doi:10.1038/nsmb.1483
A regulatable switch mediates self-association in an immunoglobulin fold
Matthew F Calabrese1, Catherine M Eakin1, Jimin M Wang1 & Andrew D Miranker1
Abstract
-2 microglobulin (2m) is a globular protein that self-associates into fibrillar amyloid deposits in patients undergoing hemodialysis therapy. Formation of these -sheet–rich assemblies is a fundamental property of polypeptides that can be triggered by diverse conditions. For 2m, oligomerization into pre-amyloidogenic states occurs in specific response to coordination by Cu2+. Here we report the basis for this self-association at atomic resolution. Metal is not a direct participant in the molecular interface. Rather, binding results in distal alterations enabling the formation of two new surfaces. These interact to form a closed hexameric species. The origins of this include isomerization of a buried and conserved cis-proline previously implicated in the 2m aggregation pathway. The consequences of this isomerization are evident and reveal a molecular basis for the conversion of this robust monomeric protein into an amyloid-competent state.
- Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, Connecticut 06520-8114, USA.
Correspondence to: Andrew D Miranker1 e-mail: andrew.miranker@yale.edu
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