Impact of Missense Variants on Protein–Protein Interactions


Single nucleotide polymorphisms (SNPs) are the most common form of human genetic variation and can affect the protein sequence. These missense variants may affect protein stability, function or interactions with other proteins, potentially leading to disease. Protein–protein interactions (PPIs) can be strengthened or weakened by missense variants, which can cause loss of salt bridges, steric clashes or changes to post‐translational modifications, amongst other effects. Changes to PPIs can lead to rewiring of the PPI network and this can be responsible for altered phenotype. Variants at different interfaces can, in some cases, lead to different phenotypes by affecting different pathways and complexes. Understanding the effects of missense variants on PPIs and the interactome is helpful in determining how these variants can lead to disease, as shown by the improved predictive performance of our variant phenotype predictor SuSPect, which includes network features.

Key Concepts:

  • Missense variants can impact upon protein–protein interactions in numerous ways.

  • Impaired or enhanced interactions can both lead to disease.

  • Interactions can be affected by steric clashes, loss of salt bridges, changes to intrinsic disorder and several other mechanisms.

  • Variants in different parts of proteins can affect different interactions, potentially leading to different diseases.

  • Variants on corresponding interfaces in different proteins can lead to the same (or similar) disease.

  • Investigating the effects of variants in the context of interaction networks rather than in isolation can give important extra information.

Keywords: missense variants; protein–protein interactions; SAV; interactome; interface; disease

Figure 1.

Structure of HLA‐DM α/β heterodimer with the βCys11‐βCys79 disulphide bond coloured yellow. Without βCys79, disulphide bonds can form between βCys11 and cysteines in the α‐subunit. This change leads to misfolded structures, causing retention of the protein in the endoplasmic reticulum and increased degradation, reducing antigen presentation.

Figure 2.

Structure of PALB2 WD40 domain showing the location of Leu939 and Leu1143 on different blades and on opposite sides of the domain. Variants of both amino acids (L939W and L1143P) affect the interaction with BRCA2, but L939W affects binding to RAD51, whereas L1143P affects interaction with RAD51C.



Adzhubei IA, Schmidt S, Peshkin L et al. (2010) A method and server for predicting damaging missense mutations. Nature Methods 7: 248–249.

Aqeilan RI and Croce CM (2007) WWOX in biological control and tumorigenesis. Journal of Cellular Physiology 212: 307–310.

Bhargava A, Voronov I, Wang Y et al. (2012) Osteopetrosis mutation R444L causes endoplasmic reticulum retention and misprocessing of vacuolar H+‐ATPase a3 subunit. Journal of Biological Chemistry 287: 26829–26839.

Bromberg Y, Kahn PC and Rost B (2013) Neutral and weakly nonneutral sequence variants may define individuality. Proceedings of the National Academy of Sciences of the USA 110: 14255–14260.

Busch R, Doebele RC, von Scheven E, Fahrni J and Mellins ED (1998) Aberrant intermolecular disulfide bonding in a mutant HLA‐DM molecule: implications for assembly, maturation, and function. Journal of Immunology 160: 734–743.

Cortese MS, Uversky VN and Dunker AK (2008) Intrinsic disorder in scaffold proteins: getting more from less. Progress in Biophysics and Molecular Biology 98: 85–106.

Das J, Mohammed J and Yu H (2012) Genome scale analysis of interaction dynamics reveals organization of biological networks. Bioinformatics 28: 1873–1878.

David A, Razali R, Wass MN and Sternberg MJE (2012) Protein‐protein interaction sites are hot spots for disease‐associated nonsynonymous SNPs. Human Mutation 33: 359–363.

De Lange WJ, Grimes AC, Hegge LF et al. (2013) E258K HCM‐causing mutation in cardiac MyBP‐C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP‐C and myosin S2 interaction. Journal of General Physiology 142: 241–255.

Ding Q, Shen Y, Yang L, Wang X and Rezaie AR (2013) The missense Thr211Pro mutation in the factor X activation peptide of a bleeding patient causes molecular defect in the clotting cascade. Thrombosis and Haemostasis 110: 53–61.

Espinosa O, Mitsopoulos K, Hakas J, Pearl F and Zvelebil M (2014) Deriving a mutation index of carcinogenicity using protein structure and protein interfaces. PLoS One 9: e84598.

George J, Motshwene PG, Wang H et al. (2011) Two human MYD88 variants, S34Y and R98C, interfere with MyD88‐IRAK4‐myddosome assembly. Journal of Biological Chemistry 286: 1341–1353.

Gsponer J and Babu MM (2009) The rules of disorder or why disorder rules. Progress in Biophysics and Molecular Biology 99: 94–103.

Guo Y, Wei X, Das J et al. (2013) Dissecting disease inheritance modes in a three‐dimensional protein network challenges the “guilt‐by‐association” principle. American Journal of Human Genetics 93: 78–89.

Hicks D, Farsani GT, Laval S et al. (2014) Mutations in the collagen XII gene define a new form of extracellular matrix‐related myopathy. Human Molecular Genetics 7–10.

Indo Y, Glassberg R, Yokota I and Tanaka K (1991) Molecular characterization of variant alpha‐subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II‐‐and identification of glycine substitution for valine‐157 in the sequence of the precursor, producing an unstable matur. American Journal of Human Genetics 49: 575–580.

Jones S and Thornton JM (1996) Principles of protein‐protein interactions. Proceedings of the National Academy of Sciences of the USA 93: 13–20.

Köhler S, Bauer S, Horn D and Robinson PN (2008) Walking the interactome for prioritization of candidate disease genes. Journal of Human Genetics 82: 949–958.

Lashuel HA, Wurth C, Woo L and Kelly JW (1999) The most pathogenic transthyretin variant, L55P, forms amyloid fibrils under acidic conditions and protofilaments under physiological conditions. Biochemistry 38: 13560–13573.

Mallaret M, Synofzik M, Lee J et al. (2013) The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain 1–9.

Ng PC and Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Research 11: 863–874.

Nicolaou N, Margadant C, Kevelam SH et al. (2012) Gain of glycosylation in integrin α 3 causes lung disease and nephrotic syndrome. Journal of Clinical Investigation 122: 4375–4387.

Nishi H, Tyagi M, Teng S et al. (2013) Cancer missense mutations alter binding properties of proteins and their interaction networks. PLoS One 8: e66273.

Pál G, Kouadio J‐LK, Artis DR, Kossiakoff AA and Sidhu SS (2006). Comprehensive and quantitative mapping of energy landscapes for protein‐protein interactions by rapid combinatorial scanning. Journal of Biological Chemistry 281: 22378–22385.

Park J‐Y, Singh TR, Nassar N et al. (2013) Breast cancer‐associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene 1–10. doi:10.1038/onc.2013.421.

Perkins JR, Diboun I, Dessailly BH, Lees JG and Orengo C (2010) Transient protein‐protein interactions: structural, functional, and network properties. Structure 18: 1233–1243.

Reva B, Antipin Y and Sander C (2011) Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Research 39: e118.

Richard P, Charron P, Carrier L et al. (2003) Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107: 2227–2232.

Schreiber G, Shaul Y and Gottschalk KE (2006) Electrostatic design of protein‐protein association rates. Methods in Molecular Biology 340: 235–249.

Shan Y, Eastwood MP, Zhang X et al. (2012) Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Cell 149: 860–870.

Sifrim A, Popovic D, Tranchevent L‐C et al. (2013) eXtasy: variant prioritization by genomic data fusion. Nature Methods 10: 1083–1084.

Szklarczyk D, Franceschini A, Kuhn M et al. (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Research 39: D561–D568.

Tennessen JA, Bigham AW, O'Connor TD et al. (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science (New York, NY) 337: 64–69.

Valdar WS and Thornton JM (2001) Protein‐protein interfaces: analysis of amino acid conservation in homodimers. Proteins: Structure, Function and Genetics 42: 108–124.

Vanunu O, Magger O, Ruppin E, Shlomi T and Sharan R (2010) Associating genes and protein complexes with disease via network propagation. PLoS Computational Biology 6: e1000641.

Wang X, Wei X, Thijssen B et al. (2012) Three‐dimensional reconstruction of protein networks provides insight into human genetic disease. Nature Biotechnology 30: 159–164.

Wang Z and Moult J (2001) SNPs, protein structure, and disease. Human Mutation 17: 263–270.

van Wijk R, Rijksen G, Huizinga EG, Nieuwenhuis HK and van Solinge WW (2003) HK Utrecht: missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia. Blood 101: 345–347.

Yates CM, Filippis I, Kelley LA and Sternberg MJE (2014) SuSPect: enhanced prediction of single amino acid variant (SAV) phenotype using network features. Journal of Molecular Biology 426(14): 2692–2701.

Yates CM and Sternberg MJE (2013) Proteins and domains vary in their tolerance of non‐synonymous single nucleotide polymorphisms (nsSNPs). Journal of Molecular Biology 425: 1274–1286.

Zhong Q, Simonis N, Li Q‐R et al. (2009) Edgetic perturbation models of human inherited disorders. Molecular Systems Biology 5: 321.

Further Reading

Chen JY, Yong E and Mooney SD (2009) Connecting protein interaction data, mutations, and disease using bioinformatics. Methods in Molecular Biology 541: 449–461.

Gulat S, Cheng TMK and Bates PA (2013) Cancer networks and beyond: interpreting mutations using the human interactome and protein structure. Seminars in Cancer Biology 23(4): 219–226.

Mosca R, Céol A and Aloy P (2013) Interactome3D: adding structural details to protein networks. Nature Methods 10: 47–53.

Schuster‐Böckler B and Bateman A (2009) Protein interactions in human genetic disease. Genome Biology 9(1): R9.

Teng S, Madej T, Panchenko A and Alexov E (2009) Modeling effects of human single nucleotide polymorphisms on protein‐protein interactions. Biophysical Journal 96(6): 2178–2188.

Yates CM and Sternberg MJ (2013) The effects of non‐synonymous single nucleotide polymorphisms (nsSNPs) on protein‐protein interactions. Journal of Molecular Biology 425(21): 3949–3963.

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Yates, Christopher M, and Sternberg, Michael JE(Aug 2014) Impact of Missense Variants on Protein–Protein Interactions. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025699]