title: Protein-protein interaction sites are hot spots for disease-associated nonsynonymous SNPs.
abstract: 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.
authors.affiliation: Centre for Integrative Systems Biology and Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: David
authors.forename: Rozami
authors.initials: R
authors.lastname: Razali
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wass
authors.forename: Michael J E
authors.initials: MJ
authors.lastname: Sternberg
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*
chemical_list: D011506:Proteins