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Raquel L. Lieberman; Molecular details of protein misfolding in myocilin-associated glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5.
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Presentation Description :
Myocilin is expressed at relatively high levels in trabecular meshwork, and missense mutations in myocilin are linked to the early-onset, hereditary form of open angle glaucoma. Using biophysical and structural methods, we have assembled a molecular picture of myocilin, including its supramolecular arrangement as defined by its coiled coil and olfactomedin protein domains, and its tendency to misfold upon mutation. Annotated glaucoma-causing variants within each structural domain exhibit vastly different protein defects. The olfactomedin domain, which harbors 90% of annotated disease variants, is exquisitely sensitive to mutation. Most olfactomedin-resident mutations are destabilizing and promote templated amyloid-like aggregation, resulting in intracellular sequestration and trabecular meshwork cytotoxicity. By contrast, the coiled coil module housing the remaining 10% of mutations largely tolerates mutations without compromising stability or causing aggregation. Selected variants within one region of the coiled coil do alter overall quaternary structure, consistent with observed partial intracellular sequestration. Taken together, our work has elaborated atomic-level details of protein misfolding relevant to the pathogenesis of myocilin-associated glaucoma.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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