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      The Contribution of Missense Mutations in Core and Rim Residues of Protein–Protein Interfaces to Human Disease

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          Abstract

          Missense mutations at protein–protein interaction sites, called interfaces, are important contributors to human disease. Interfaces are non-uniform surface areas characterized by two main regions, “core” and “rim”, which differ in terms of evolutionary conservation and physicochemical properties. Moreover, within interfaces, only a small subset of residues (“hot spots”) is crucial for the binding free energy of the protein–protein complex.

          We performed a large-scale structural analysis of human single amino acid variations (SAVs) and demonstrated that disease-causing mutations are preferentially located within the interface core, as opposed to the rim ( p < 0.01). In contrast, the interface rim is significantly enriched in polymorphisms, similar to the remaining non-interacting surface. Energetic hot spots tend to be enriched in disease-causing mutations compared to non-hot spots ( p = 0.05), regardless of their occurrence in core or rim residues. For individual amino acids, the frequency of substitution into a polymorphism or disease-causing mutation differed to other amino acids and was related to its structural location, as was the type of physicochemical change introduced by the SAV.

          In conclusion, this study demonstrated the different distribution and properties of disease-causing SAVs and polymorphisms within different structural regions and in relation to the energetic contribution of amino acid in protein–protein interfaces, thus highlighting the importance of a structural system biology approach for predicting the effect of SAVs.

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          Highlights

          • Protein–protein interactions are fundamental in all biological processes.

          • The distribution of deleterious and non-SAVs within protein interfaces is unknown.

          • The distribution of deleterious SAVs differs within different interface structural regions.

          • The distribution of SAVs differs in relation to interface residues energetic contribution.

          • Structural analysis of protein complexes enhances the understanding of deleterious SAVs.

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          Most cited references42

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          Amino acid substitution matrices from protein blocks.

          Methods for alignment of protein sequences typically measure similarity by using a substitution matrix with scores for all possible exchanges of one amino acid with another. The most widely used matrices are based on the Dayhoff model of evolutionary rates. Using a different approach, we have derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins. This led to marked improvements in alignments and in searches using queries from each of the groups.
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            Activities at the Universal Protein Resource (UniProt)

            The mission of the Universal Protein Resource (UniProt) (http://www.uniprot.org) is to provide the scientific community with a comprehensive, high-quality and freely accessible resource of protein sequences and functional annotation. It integrates, interprets and standardizes data from literature and numerous resources to achieve the most comprehensive catalog possible of protein information. The central activities are the biocuration of the UniProt Knowledgebase and the dissemination of these data through our Web site and web services. UniProt is produced by the UniProt Consortium, which consists of groups from the European Bioinformatics Institute (EBI), the SIB Swiss Institute of Bioinformatics (SIB) and the Protein Information Resource (PIR). UniProt is updated and distributed every 4 weeks and can be accessed online for searches or downloads.
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              The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data

              The worldwide Protein Data Bank (wwPDB) is the international collaboration that manages the deposition, processing and distribution of the PDB archive. The online PDB archive is a repository for the coordinates and related information for more than 38 000 structures, including proteins, nucleic acids and large macromolecular complexes that have been determined using X-ray crystallography, NMR and electron microscopy techniques. The founding members of the wwPDB are RCSB PDB (USA), MSD-EBI (Europe) and PDBj (Japan) [H.M. Berman, K. Henrick and H. Nakamura (2003) Nature Struct. Biol., 10, 980]. The BMRB group (USA) joined the wwPDB in 2006. The mission of the wwPDB is to maintain a single archive of macromolecular structural data that are freely and publicly available to the global community. Additionally, the wwPDB provides a variety of services to a broad community of users. The wwPDB website at provides information about services provided by the individual member organizations and about projects undertaken by the wwPDB.
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                Author and article information

                Contributors
                Journal
                J Mol Biol
                J. Mol. Biol
                Journal of Molecular Biology
                Elsevier
                0022-2836
                1089-8638
                28 August 2015
                28 August 2015
                : 427
                : 17
                : 2886-2898
                Affiliations
                Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, SW7 2AZ London, United Kingdom
                Author notes
                [* ]Corresponding author. Centre for Integrative Systems Biology and Bioinformatics, Sir Ernst Chain Building, Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom. alessia.david09@ 123456imperial.ac.uk
                Article
                S0022-2836(15)00382-4
                10.1016/j.jmb.2015.07.004
                4548493
                26173036
                9c7b0bad-f6ba-415b-8b55-8d3da4b472c0
                © 2015 The Authors. Published by Elsevier Ltd.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 1 May 2015
                : 19 June 2015
                : 6 July 2015
                Categories
                Article

                Molecular biology
                asmt, acetyl serotonin o-methyltransferase,pdb, protein data bank,spt, serine pyruvate aminotransferase,plce1, 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1,ppi, protein–protein interaction,sav, single amino acid variation,sse, secondary structure elements,protein–protein interaction,core and rim interface,human disease,savs,nssnps

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