Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health

Abstract

Many essential biological processes including cell regulation and signalling are mediated through the assembly of protein complexes. Changes to protein-protein interaction (PPI) interfaces can affect the formation of multiprotein complexes, and consequently lead to disruptions in interconnected networks of PPIs within and between cells, further leading to phenotypic changes as functional interactions are created or disrupted. Mutations altering PPIs have been linked to the development of genetic diseases including cancer and rare Mendelian diseases, and to the development of drug resistance. The importance of these protein mutations has led to the development of many resources for understanding and predicting their effects. We propose that a better understanding of how these mutations affect the structure, function, and formation of multiprotein complexes provides novel opportunities for tackling them, including the development of small-molecule drugs targeted specifically to mutated PPIs.

Keywords: Drug development; Mutations; Protein interaction; Protein stability; Protein-protein interfaces.