Protein-protein interaction sites are hot spots for disease-associated nonsynonymous SNPs

Hum Mutat. 2012 Feb;33(2):359-63. doi: 10.1002/humu.21656. Epub 2011 Dec 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Binding Sites / genetics
  • Humans
  • Models, Molecular
  • Polymorphism, Single Nucleotide*
  • Protein Binding / physiology
  • Protein Conformation
  • Protein Interaction Domains and Motifs / genetics*
  • Proteins / chemistry*
  • Proteins / genetics*


  • Proteins