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.

Docking features for predicting binding loss due to protein mutation

“…For example, in a structural survey of nsSNPs, Wang et al (2012) [8] showed that those associated with disease tend to localize to protein interaction interfaces, when found at the protein surface. This finding, which was corroborated by a similar study from the same year [9], builds upon the earlier finding [10] that disease-nsSNPs tend to cluster together, when present at the surface of proteins. In support of a differential distribution of disease and non-disease causing polymorphisms, Wang et al (2012) [8] found that nondisease nsSNPs showed no greater tendency than average to localize to interfaces in the largest human structural interaction network developed to date (4222 interfaces between 2816 proteins).…”

Combining Structural Modeling with Ensemble Machine Learning to Accurately Predict Protein Fold Stability and Binding Affinity Effects upon Mutation

“…Many disease-related mutations have been found at the interface of protein complexes [32], [33]. These mutations can disrupt protein-protein interactions, affecting signalling pathways and leading to diseases.…”

“…In globular domains, the effect of each mutation is determined by its structural context; whereas mutations in the core may alter the stability of the domain fold, mutations at the surface regions that are involved in molecular recognition may directly affect binding affinities. In fact, many, if not most, disease-related mutations are located at the interface of protein complexes [32], [33]. A small subset of interface residues, called hot spots, are critical for complex formation and their identification is of major importance.…”

Protein–protein interaction networks studies and importance of 3D structure knowledge

“…The importance of interfaces for protein functions and biological processes was further confirmed in recent studies by looking at the occurrences of disease-associated mutations [26,106], where the interface regions were found to be enriched in disease-causing mutations. This implies that a residue change at these region is more likely to disrupt protein functions and lead to diseases.…”