8frr
Wild-type myocilin olfactomedin domain
Structural highlights
Publication Abstract from PubMedStudies 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 adopt distinct partially folded structures seen along the OLF(WT) 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. Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming beta-propeller.,Saccuzzo EG, Mebrat MD, Scelsi HF, Kim M, Ma MT, Su X, Hill SE, Rheaume E, Li R, Torres MP, Gumbart JC, Van Horn WD, Lieberman RL Nat Commun. 2024 Jan 2;15(1):155. doi: 10.1038/s41467-023-44479-2. PMID:38168102[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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