Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 15, Issue 9, Pages 965-971Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1483
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Funding
- US National Institutes of Health [DK54899, 5T32GM07223]
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beta-2 microglobulin (beta 2m) is a globular protein that self-associates into fibrillar amyloid deposits in patients undergoing hemodialysis therapy. Formation of these beta-sheet-rich assemblies is a fundamental property of polypeptides that can be triggered by diverse conditions. For beta 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 beta 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.
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