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

Authors

  • Alessia David,

    1. Centre for Integrative Systems Biology and Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
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  • Rozami Razali,

    1. Centre for Integrative Systems Biology and Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
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  • Mark N. Wass,

    Corresponding author
    1. Centre for Integrative Systems Biology and Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
    • Centre for Integrative Systems Biology and Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK

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    • These authors contributed equally to this work and should be considered joint last authors.

  • Michael J.E. Sternberg

    Corresponding author
    1. Centre for Integrative Systems Biology and Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
    • Centre for Integrative Systems Biology and Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK

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    • These authors contributed equally to this work and should be considered joint last authors.


  • Communicated by Mauno Vihinen

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. Hum Mutat 33:359–363, 2012. © 2011 Wiley Periodicals, Inc.

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