Protein-Protein Interaction Sites are Hot Spots for Disease-Associated Nonsynonymous SNPs

被引:126
作者
David, Alessia [1 ]
Razali, Rozami [1 ]
Wass, Mark N. [1 ]
Sternberg, Michael J. E. [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Div Mol Biosci, Ctr Integrat Syst Biol & Bioinformat, London SW7 2AZ, England
基金
英国生物技术与生命科学研究理事会;
关键词
nonsynonymous SNPs; protein structure; interactome; bioinformatics; HYPERTROPHIC CARDIOMYOPATHY; INTERACTION DATABASE; MISSENSE MUTATIONS; ELECTRON-TRANSFER; POLYMORPHISMS; DOMAIN; IDENTIFICATION; FLAVOPROTEIN; SUBSTITUTION; PREDICTION;
D O I
10.1002/humu.21656
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Many nonsynonymous single nucleotide polymorphisms (nsSNPs) are disease causing due to effects at protein-protein interfaces. We have integrated a database of the three-dimensional (3D) structures of human protein/protein complexes and the humsavar database of nsSNPs. We analyzed the location of nsSNPS in terms of their location in the protein core, at protein-protein interfaces, and on the surface when not at an interface. Disease-causing nsSNPs that do not occur in the protein core are preferentially located at protein-protein interfaces rather than surface noninterface regions when compared to random segregation. The disruption of the protein-protein interaction can be explained by a range of structural effects including the loss of an electrostatic salt bridge, the destabilization due to reduction of the hydrophobic effect, the formation of a steric clash, and the introduction of a proline altering the main-chain conformation. Hum Mutat 33:359-363, 2012. (C) 2011 Wiley Periodicals, Inc.
引用
收藏
页码:359 / 363
页数:5
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