Global computational mutagenesis of domain structures associated with inherited eye disease.
Sci Rep
; 9(1): 3676, 2019 03 06.
Article
in En
| MEDLINE
| ID: mdl-30842450
ABSTRACT
Multidomain proteins account for 70% of the eukaryotic proteome. In genetic disease, multidomain proteins are often affected by numerous mutations, but the effects of these mutations on protein stability and their roles in genetic disease are not well understood. Here, we analyzed protein globular domains to understand how genetic mutations affect the stability of multidomain proteins in inherited disease. In total, 291 domain atomic structures from nine multidomain proteins were modeled by homology, equilibrated using molecular dynamics in water, and subjected to global computational mutagenesis. The domains were separated into 7 groups based on protein fold homology. Mutation propensities within each group of domains were then averaged to select residues critical for domain fold stability. The consensus derived from the sequence alignment shows that the critical residues determined by global mutagenesis are conserved within each group. From this analysis, we concluded that 80% of known disease-related genetic variants are associated with critical residues and are expected to have significant destabilizing effects on domain structure. Our work provides an in silico quantification of protein stability and could help to analyze the complex relationship among missense mutations, multidomain protein stability, and disease phenotypes in inherited eye disease.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Eye Diseases, Hereditary
/
Protein Domains
/
Mutation
Type of study:
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Sci Rep
Year:
2019
Document type:
Article
Affiliation country:
United States