Amyloid fibril formation by the glaucoma-associated olfactomedin domain of myocilin.

TitleAmyloid fibril formation by the glaucoma-associated olfactomedin domain of myocilin.
Publication TypeJournal Article
Year of Publication2012
AuthorsOrwig, SD, Perry, CW, Kim, LY, Turnage, KC, Zhang, R, Vollrath, D, Schmidt-Krey, I, Lieberman, RL
JournalJ Mol Biol
Volume421
Issue2-3
Pagination242-55
Date Published2012 Aug 10
ISSN1089-8638
KeywordsAmino Acid Sequence, Amyloid, Biophysics, Cytoskeletal Proteins, Escherichia coli, Extracellular Matrix Proteins, Eye Proteins, Glaucoma, Glycoproteins, Humans, Molecular Sequence Data, Sequence Homology, Amino Acid
Abstract

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.

DOI10.1016/j.jmb.2011.12.016
Alternate JournalJ. Mol. Biol.
PubMed ID22197377
PubMed Central IDPMC3323732
Grant ListR01 EY011405 / EY / NEI NIH HHS / United States
R01 EY011405-11 / EY / NEI NIH HHS / United States
R01 EY021205 / EY / NEI NIH HHS / United States
R01 EY021205-01 / EY / NEI NIH HHS / United States
R01EY011405 / EY / NEI NIH HHS / United States
R01EY021205 / EY / NEI NIH HHS / United States