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Yuri Sergeev, Francisca Wood Ortiz, Mikhail Laryukhin, Caitlyn McCafferty; Global computational mutagenesis of ocular proteome indicates a role of protein destabilization in inherited eye disease.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2365.
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© ARVO (1962-2015); The Authors (2016-present)
Many genetic eye diseases are associated with genetic mutations that effect protein structure. The understanding of the mutation significance is important for genetic disease. Current computational tools for analysis of mutation effect are disregarding the protein atomic structure. Here, global computational mutagenesis from atomic level of protein structure was applied to ocular disease proteome to show a role of protein structure/stability in genetic disorder.
Proteins from inherited eye diseases were obtained by homology modeling using crystal structures from the PDB database as structural templates. Each protein was treated using a global computational mutagenesis to evaluate changes in protein stability for any possible missense mutation structure and to identify the critical changes that cannot tolerate a substitution without causing protein misfolding (McCafferty & Sergeev, 2016). A critical protein stability framework identified by selection of critical changes in protein structure (McCaffery & Sergeev, 2017). The protein data were annotated using information from the Genetics Home Reference and UniProt databases.
Currently, 90 proteins associated with 133 eye diseases were modeled and included in the database of ocular proteome, which is freely available at (http://profold.nei.nih.gov). Changes in protein stability were evaluated from atomic level of protein structure for ~1,000,000 missense mutations. In average, 21.8±9.2% of mutations in protein structure found to be critical for protein stability. The highest fraction of critical structure (>35%) was found for Greek key, 4-bundle, and 7 β-propeller domains. Protein destabilization, which determined computationally using unfolding mutation screen showed an association with clinical parameters for several proteins from retinal disorder.
Global computational mutagenesis suggests a significant number of residues involved in the critical protein stability framework. The database of ocular proteome comprises information on protein structure, function, protein stability framework, and phenotypes for ocular disease related proteins. This could be useful in protein design, the express-analysis of mutation severity, genotype-to-phenotype associations, and the analysis of next-generation sequencing data.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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