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

Saccuzzo, Emily G.; Mebrat, Mubark D.; Scelsi, Hailee F.; Kim, Minjoo; Ma, Minh Thu; Su, Xinya; Hill, Shannon E.; Rheaume, Elisa; Li, Renhao; Torres, Matthew P.; Gumbart, James C.; Van Horn, Wade D.; Lieberman, Raquel L.

doi:10.1038/s41467-023-44479-2

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

Journal Article · Tue Jan 02 00:00:00 EST 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-44479-2· OSTI ID:2470105

Saccuzzo, Emily G. ^[1]; Mebrat, Mubark D. ^[2]; Scelsi, Hailee F. ^[1]; ^[2]; Ma, Minh Thu ^[1]; Su, Xinya ^[1]; Hill, Shannon E. ^[1]; Rheaume, Elisa ^[1]; ^[3]; Torres, Matthew P. ^[1]; Gumbart, James C. ^[1]; ^[2]; ^[1]

Georgia Institute of Technology, Atlanta, GA (United States)
Arizona State Univ., Tempe, AZ (United States)
Emory Univ., Atlanta, GA (United States)

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 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357; W-31109-ENG-38

OSTI ID:: 2470105

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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

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