A regulatable switch mediates self-association in an immunoglobulin fold.
Beta-2 microglobulin (beta2m) 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 beta2m, 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 beta2m 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.
Calabrese
Matthew F
MF
Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, Connecticut 06520-8114, USA.
Eakin
Catherine M
CM
Wang
Jimin M
JM
Miranker
Andrew D
AD
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D018360:Crystallography, X-Ray; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007136:Immunoglobulins / Q000737:chemistry* / Q000378:metabolism; D066298:In Vitro Techniques; D008954:Models, Biological; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D006435:Renal Dialysis / Q000009:adverse effects; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D007136:Immunoglobulins; D046912:Multiprotein Complexes; D001613:beta 2-Microglobulin; D003300:Copper