8frr | pdb_00008frr
Wild-type myocilin olfactomedin domain
Structural highlights
DiseaseMYOC_HUMAN Congenital glaucoma;Juvenile glaucoma. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. MYOC mutations may contribute to GLC3A via digenic inheritance with CYP1B1 and/or another locus associated with the disease (PubMed:15733270).[1] FunctionMYOC_HUMAN Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.[2] [3] [4] [5] [6] [7] [8] [9] 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[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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