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 (OLFWT) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLFD380A) and severe (OLFI499F) disease variants aggregate differently, with rates comparable to OLFWT in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLFWT urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation.

Unlocking data inKlebsiellalysogens to predict capsular type-specificity of phage depolymerases

“…Pan et al 2017). In contrast, while ongoing research explores the properties of the n-bladed β-propeller in bacteria and eukaryotes (Saccuzzo et al 2024;C. Chen et al 2024), its characteristics in phages remain unclear.…”