Structural and biophysical characterization of the myocilin olfactomedin domain
Donegan, Rebecca Kristen
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The myocilin olfactomedin domain (myoc-OLF) is linked to inherited forms of open angle glaucoma. Mutant myocilin accumulates within the endoplasmic reticulum of human trabecular meshwork cells leading to cell death and the build up of intraocular pressure, a common risk factor for glaucoma. In this work, a novel high affinity calcium-binding site buried within myoc-OLF was characterized. Additionally amyloidogenic peptide stretches within myoc-OLF that may be responsible for mutant myocilin aggregation were determined. Additionally the crystal structure of myoc-OLF was solved providing the first crystal structure of an olfactomedin domain protein. Insights from the structure into the relationship between disease causing mutations and myoc-OLF misfolding and the currently unknown function of myoc-OLF as explored by structural based prediction of ligand binding are also discussed.