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Abstract #48838 Published in IGR 14-1
Amyloid Fibril Formation by the Glaucoma-Associated Olfactomedin Domain of Myocilin
Orwig SD; Perry CW; Kim LY; Turnage KC; Zhang R; Vollrath D; Schmidt-Krey I; Lieberman RLJournal of Molecular Biology 2012; 421: 242-255
Myocilin is a protein found in the extracellular matrix of trabecular meshwork tissue, the anatomical region of the eye involved in regulating intraocular pressure. Wild-type (WT) myocilin has been associated with steroid-induced glaucoma, and variants of myocilin have been linked to early-onset inherited glaucoma. Elevated levels and aggregation of myocilin hasten increased intraocular pressure and glaucoma-characteristic vision loss due to irreversible damage to the optic nerve. In spite of reports on the intracellular accumulation of mutant and WT myocilin in vitro, cell culture, and model organisms, these aggregates have not been structurally characterized. In this work, we provide biophysical evidence for the hallmarks of amyloid fibrils in aggregated forms of WT and mutant myocilin localized to the C-terminal olfactomedin (OLF) domain. These fibrils are grown under a variety of conditions in a nucleation-dependent and self-propagating manner. Protofibrillar oligomers and mature amyloid fibrils are observed in vitro. Full-length mutant myocilin expressed in mammalian cells forms intracellular amyloid-containing aggregates as well. Taken together, this work provides new insights into and raises new questions about the molecular properties of the highly conserved OLF domain, and suggests a novel protein-based hypothesis for glaucoma pathogenesis for further testing in a clinical setting.
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA.
Full articleClassification:
3.5 Molecular biology incl. SiRNA (Part of: 3 Laboratory methods)
