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

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.

Keywords: SAVs; core and rim interface; human disease; nsSNPs; protein–protein interaction.

Graphical abstract

Fig. 1

Schematic diagram of core and rim interface regions. Highlighted is a cross-sectional view of a protein–protein interface. Interacting proteins are presented in light and dark gray, respectively. The interface core is presented in orange and the rim is presented in blue.

Fig. 2

Distribution of the percentages of BLOSUM62, Grantham and SIFT scores for 3282 disease-causing SAVs and 1699 polymorphisms according to their location in different protein regions. Substitutions were characterized as “damaging” according to the following parameters: Grantham score > 60, BLOSUM62 score < 0 and SIFT score ≤ 0.10. *, Bonferroni-corrected p value of < 0.05 ; **, Bonferroni-corrected p value of < 0.01.

Fig. 3

Amino acid susceptibility to disease-causing SAVs or polymorphisms according to structural location. The percentages of disease-causing SAVs (striped boxes) and polymorphisms (uniform dark-gray boxes) harbored by each amino acid across the entire protein (“All”) and within the four structural regions of the protein, that is, buried (Buried), interface core (Core), interface rim (Rim) and non-interacting surface (Surface), are shown.

Fig. 4

Distribution of the physicochemical changes introduced by SAVs. Changes were evaluated in terms of hydrophobicity, charge or polarity loss and charge change across the different protein regions and overall (All). Data were analyzed for disease-causing SAVs and polymorphisms. D, disease-causing SAVs; P, polymorphisms. Surface, non-interacting surface.

Fig. 5

Interface rim SAVs associated with disease. (a) Mutation p.Glu63Lys. The wild-type glutamic acid 63 located at the interface rim of the GTPase HRAS protein is presented in blue and the interacting lysine on protein PLCE1 is presented in magenta (PDB ID: 2c5l). (b) Polymorphism p.Arg115Trp (dbSNP: rs201053197). The water-mediated interaction between wild-type arginines 115 at the ASMT homodimer interface is shown. Interacting arginines are presented in magenta and water molecules are presented as blue spheres (PDB ID: 4a6d). The two chains of the interacting proteins are presented in green and gray in both cases. Distances between atoms of two interacting residues are calculated in angstroms (Å).