Nature Structural & Molecular Biology 13, 202 - 208 (2006)
Published online: 19 February 2006; | doi:10.1038/nsmb1068
A native to amyloidogenic transition regulated by a backbone triggerCatherine M Eakin1, 2, Andrea J Berman1
& Andrew D Miranker11
Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, Connecticut 06520-8114, USA. 2
Present address: Department of Biochemistry and Biomolecular Structure Center, University of Washington, K464 Health Science Building, Box 357350, Seattle, Washington, 98195-7742, USA.
Correspondence should be addressed to Andrew D Miranker andrew.miranker@yale.edu Many polypeptides can self-associate into linear, aggregated assemblies termed amyloid fibers. High-resolution structural insights into the mechanism of fibrillogenesis are elusive owing to the transient and mixed oligomeric nature of assembly intermediates. Here, we report the conformational changes that initiate fiber formation by  -2-microglobulin (2m) in dialysis-related amyloidosis. Access of 2m to amyloidogenic conformations is catalyzed by selective binding of divalent cations. The chemical basis of this process was determined to be backbone isomerization of a conserved proline. On the basis of this finding, we designed a 2m variant that closely adopts this intermediate state. The variant has kinetic, thermodynamic and catalytic properties consistent with its being a fibrillogenic intermediate of wild-type 2m. Furthermore, it is stable and folded, enabling us to unambiguously determine the initiating conformational changes for amyloid assembly at atomic resolution.
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