A native to amyloidogenic transition regulated by a backbone trigger.

Article Details

Citation

Eakin CM, Berman AJ, Miranker AD

A native to amyloidogenic transition regulated by a backbone trigger.

Nat Struct Mol Biol. 2006 Mar;13(3):202-8. Epub 2006 Feb 19.

PubMed ID
16491088 [ View in PubMed
]
Abstract

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 beta-2-microglobulin (beta2m) in dialysis-related amyloidosis. Access of beta2m 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 beta2m 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 beta2m. Furthermore, it is stable and folded, enabling us to unambiguously determine the initiating conformational changes for amyloid assembly at atomic resolution.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Beta-2-microglobulinP61769Details