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Yuri V Sergeev; Molecular Modeling of USH2A Domains and Structural Significance of Genetic Changes in Usher Disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3272.
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Genetic mutations in the USH2A gene cause the Usher syndrome type II which affects hearing and vision. The Usher syndrome type-2A encodes a structural protein important in development and maintenance of the inner ear and neural retinal. Here we apply molecular modeling to obtain the atomic structures of the USH2A domains and analyze the functional significance of mutant variants associated with Usher’s disease.
The 5202 amino acid USH2A sequence was selected from the UniProtKB database (acc. #O75445). The repetitive protein domains of USH2A (e.g., the 10 laminin EGF-like domains and the 35 fibronectin type-III domains) were multiple-aligned by Promals3D to show the conserved sequence patterns at the domain sequence-structure template. Disease-causing missense mutations were selected from the Retinal and hearing impairment genetic mutation database (LOVD). Atomic structures of protein domains affected by genetic mutations were modeled by homology, refined, and 3ns equilibrated using molecular dynamics at 37oC.
The multiple sequence alignment and analysis of domain atomic structure confirmed that the laminin EGF-like domain has 8 highly conserved cysteines that form 4 S-S-bridges to stabilize the native domain folding. In contrast, no cysteine residues are involved in the fibronectin type-III domain stabilization. In addition, these domain structures have no highly conserved residues and are stabilized by multiple prolines and hydrophobic interactions at the N-terminus. The conserved sequence/3D-structure pattern has been analyzed in USH2A domains in order to evaluate the severity of mutant variants in Usher’s disease.
The analysis of the domain sequence-structure templates could significantly accelerate the analysis severity of mutant variants in large proteins with repetitive structure. This could be a useful tool for the functional annotation of genetic variants from next-generation sequencing data and establishing the genotype-to-phenotype relationships in genetic disease.
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