Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller.

ABSTRACT: Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF^WT) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF^D380A) and severe (OLF^I499F) disease variants aggregate differently, with rates comparable to OLF^WT in initial stages of unfolding, and variants adop

SUBMITTER: Saccuzzo EG 

PROVIDER: S-EPMC10762032 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature