A covalent homodimer probing early oligomers along amyloid aggregation.

ABSTRACT: Early oligomers are crucial in amyloid aggregation; however, due to their transient nature they are among the least structurally characterized species. We focused on the amyloidogenic protein beta2-microglobulin (?2m) whose early oligomers are still a matter of debate. An intermolecular interaction between D strands of facing ?2m molecules was repeatedly observed, suggesting that such interface may be relevant for ?2m dimerization. In this study, by mutating Ser33 to Cys, and assembling the disulphide-stabilized ?2m homodimer (DimC33), such DD strand interface was locked. Although the isolated DimC33 display a stability similar to wt ?2m under native conditions, it shows enhanced amyloid aggregation propensity. Three distinct crystal structures of DimC33 suggest that dimerization through the DD interface is instrumental for enhancing DimC33 aggregation propensity. Furthermore, the crystal structure of DimC33 in complex with the amyloid-specific dye Thioflavin-T pinpoints a second interface, which likely participates in the first steps of ?2m aggregation. The present data provide new insight into ?2m early steps of amyloid aggregation.

SUBMITTER: Halabelian L 

PROVIDER: S-EPMC4588566 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature