A regulatable switch mediates self-association in an immunoglobulin fold

作者：Calabrese Matthew F; Eakin Catherine M; Wang Jimin M; Miranker Andrew D^*

来源：Nature Structural & Molecular Biology, 2008, 15(9): 965-971.

DOI：10.1038/nsmb.1483

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 Cu(2+). 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.

• 出版日期2008-9