Impact of Missense Variants on Protein–Protein Interactions

Abstract

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.

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Further Reading

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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. http://www.els.net [doi: 10.1002/9780470015902.a0025699]