Structure, dynamics, and misfolding of the glaucoma-associated myocilin olfactomedin domain: How a protein’s structure spells the difference between health and disease

Mutations within the olfactomedin domain of myocilin (OLF) cause cytotoxic amyloid-like aggregation in the endoplasmic reticulum, which in turn hasten the progression of vision loss due to glaucoma. Despite progress in molecular characterization of OLF at a molecular level, differentiating disease from benign mutations remains a challenge. In this talk I will present recent findings from my lab on the emerging relationship between OLF unfolding and aggregation and how this relationship may relate to its pathogenic misfolding. Broadly, our study of myocilin illustrates complexities introduced by large amyloid-forming proteins when undergoing folded-to-misfolded transitions compared to smaller model amyloid systems.