Differential Misfolding Properties of Glaucoma-Associated Olfactomedin Domains from Humans and Mice

Biochemistry
Athéna C Patterson-OrazemRaquel L Lieberman

Abstract

Mutations in myocilin, predominantly within its olfactomedin (OLF) domain, are causative for the heritable form of open angle glaucoma in humans. Surprisingly, mice expressing Tyr423His mutant myocilin, corresponding to a severe glaucoma-causing mutation (Tyr437His) in human subjects, exhibit a weak, if any, glaucoma phenotype. To address possible protein-level discrepancies between mouse and human OLFs, which might lead to this outcome, biophysical properties of mouse OLF were characterized for comparison with those of human OLF. The 1.55 Å resolution crystal structure of mouse OLF reveals an asymmetric 5-bladed β-propeller that is nearly indistinguishable from previous structures of human OLF. Wild-type and selected mutant mouse OLFs mirror thermal stabilities of their human OLF counterparts, including characteristic stabilization in the presence of calcium. Mouse OLF forms thioflavin T-positive aggregates with a similar end-point morphology as human OLF, but amyloid aggregation kinetic rates of mouse OLF are faster than human OLF. Simulations and experiments support the interpretation that kinetics of mouse OLF are faster because of a decreased charge repulsion arising from more neutral surface electrostatics. Taken together...Continue Reading

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Citations

Nov 16, 2019·BMC Molecular and Cell Biology·Matti F PronkerBert J C Janssen
Apr 14, 2021·Accounts of Chemical Research·Raquel L Lieberman, Minh Thu Ma
Dec 20, 2021·Human Mutation·Edward Ryan A CollantesJaney L Wiggs

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