ArticleJournal of molecular biology2015
The Contribution of Missense Mutations in Core and Rim Residues of Protein-Protein Interfaces to Human Disease.
Article in Journal of molecular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed.
- A simple probabilistic AlphaFold interaction score.Protein science : a publication of the Protein Society · 2026Article
- Clinical and molecular characterization of giant axonal neuropathy due to a homozygous c.851 + 1G>A variant inGlobal medical genetics · 2026Article
- Elucidation of DNA Primase as a Drug Target in Leishmania donovani: Structure-Guided Inhibitor Identification and Biochemical Validation.Chemical biology & drug design · 2026Article
- Classification of driver and passenger mutations in different cancer types using deep neural networks.Bioinformatics advances · 2026Article
- Co-Var, a Measure to Determine Intra-protein, Inter-protein, Protein-DNA, or Protein-RNA Coevolution.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Calibrated Variant Effect Prediction at the Residue Level Using Conditional Score Distributions.bioRxiv : the preprint server for biology · 2025Article
- PLM-interact: extending protein language models to predict protein-protein interactions.Nature communications · 2025Article
- PRESCOTT: a population aware, epistatic, and structural model accurately predicts missense effects.Genome biology · 2025Article
- Disentangling the mutational effects on protein stability and interaction of human MLH1.PLoS genetics · 2025Article
- Decoding the functional impact of the cancer genome through protein-protein interactions.Nature reviews. Cancer · 2025Review
- Restoring adapter protein complex 4 function with small molecules: an in silico approach to spastic paraplegia 50.Protein science : a publication of the Protein Society · 2025Article
- Genetic variants associated with age-related episodic memory decline implicate distinct memory pathologies.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Challenges in bridging the gap between protein structure prediction and functional interpretation.Proteins · 2025Article
- Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.Molecular systems biology · 2024Article
- MTR3D-AF2: Expanding the coverage of spatially derived missense tolerance scores across the human proteome using AlphaFold2.Protein science : a publication of the Protein Society · 2024Article
- A unified analysis of evolutionary and population constraint in protein domains highlights structural features and pathogenic sites.Communications biology · 2024Article
- Article
- Review of Computational Methods and Database Sources for Predicting the Effects of Coding Frameshift Small Insertion and Deletion Variations.ACS omega · 2024Review
- Software for Predicting Binding Free Energy of Protein-Protein Complexes and Their Mutants.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Exploring Novel Variants of the Cytochrome P450 Reductase Gene (Biomolecules · 2023Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors.
Funding
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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