A simulated intermediate state for folding and aggregation provides insights into ?N6 ?2-microglobulin amyloidogenic behavior.

ABSTRACT: A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of ?2-microglobulin (?N6) lacking the first six N-terminal residues. Here we perform a computational study on ?N6, which provides clues to understand the amyloidogenicity of the full-length ?2-microglobulin. Contrary to the wild-type form, ?N6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in ?N6 amyloidogenesis.

SUBMITTER: Estacio SG 

PROVIDER: S-EPMC4014404 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature