A covalent homodimer probing early oligomers along amyloid aggregation

作者：Halabelian Levon; Relini Annalisa; Barbiroli Alberto; Penco Amanda; Bolognesi Martino; Ricagno Stefano^*

来源：Scientific Reports, 2015, 5(1): 14651.

DOI：10.1038/srep14651

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 (beta 2m) whose early oligomers are still a matter of debate. An intermolecular interaction between D strands of facing beta 2m molecules was repeatedly observed, suggesting that such interface may be relevant for beta 2m dimerization. In this study, by mutating Ser33 to Cys, and assembling the disulphide-stabilized beta 2m homodimer (DimC33), such DD strand interface was locked. Although the isolated DimC33 display a stability similar to wt beta 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 beta 2m aggregation. The present data provide new insight into beta 2m early steps of amyloid aggregation.

• 出版日期2015-9-30