Abstract
β-2 microglobulin (β2m) is a globular protein that self-associates into fibrillar amyloid deposits in patients undergoing hemodialysis therapy. Formation of these β-sheet–rich assemblies is a fundamental property of polypeptides that can be triggered by diverse conditions. For β2m, 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 β2m 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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Acknowledgements
We thank D.M. Engelman, A. Schepartz and G.W. Brudvig for use of instruments and the staff of the Center for Structural Biology and National Synchotron Light Source (NSLS) beamline X12B for assistance and helpful discussions. We are also grateful to Y. Xiong, Y. Modis, A. Berman, A. Valentine, S.A. Strobel, J.C. Cochrane, C. Craig, D.V. Blaho and A.O. Olivares for assistance and comments. This work was supported by the US National Institutes of Health (DK54899 and 5T32GM07223).
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M.F.C., C.M.E. and A.D.M. designed the experiments; M.F.C. conducted the experiments; M.F.C. and J.M.W. solved and refined the structure; M.F.C. and A.D.M. wrote the paper.
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Calabrese, M., Eakin, C., Wang, J. et al. A regulatable switch mediates self-association in an immunoglobulin fold. Nat Struct Mol Biol 15, 965–971 (2008). https://doi.org/10.1038/nsmb.1483
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DOI: https://doi.org/10.1038/nsmb.1483
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