Insights into disease-associated mutations in the human proteome through protein structural analysis
Open accessAbstract
Most known disease-associated mutations are missense mutations involving changes of amino acids of proteins encoded by their genes. Given the plethora of genetic studies, sequenced exomes, and new protein structures determined each year, it is appropriate to revisit the role that structure plays in providing insights into the molecular basis of disease-associated mutations. In that regard, a large-scale structural analysis of 6,025 disease-associated mutations as well as 4,536 neutral variations for comparison was performed. While buried amino acids are common among the disease-associated mutations, as reported previously, more are statistically significantly enriched at observed or predicted functional sites. Interesting findings are that ligand-binding sites adjacent to protein-protein interfaces and residues involved in enzymatic function are especially vulnerable to disease-associated mutations. Finally, a compositional analysis of disease-associated mutations in comparison with variants identified in the 1000 Genomes Project provides a structural rationalization of the most disease-associated residue types.
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Single-point mutations can affect protein-protein interactions via different molecular mechanisms, including changing folding free energy of interacting partners or disrupting non-covalent interactions essential for complex formation.
“Single-point mutations can affect protein–protein interactions via different molecular mechanisms, including changing folding free energy of interacting partners or disrupting non-covalent interactions essential for complex formation (6,43).”
From mCSM-PPI2: predicting the effects of mutations on protein–protein interactions (2019) · cites this paper as [6]
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mCSM-PPI2: predicting the effects of mutations on protein–protein interactions
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Self-citation
- Authors
- Gao, M., Zhou, H., & Skolnick, J.
- Affiliations
- Georgia Institute of Technology (US)
- Corresponding author
- Skolnick, Jeffrey
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 23
- Issue
- 7
- Pages
- 1362-1369
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC4497952
- OpenAlex
- W1935098740
- Cited by
- 113
- References
- 26
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 8 · 2023: 7 · 2022: 15 · 2021: 15 · 2020: 11 · 2019: 18 · 2018: 9 · 2017: 5 · 2016: 8 · 2015: 3
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (GM 37408, R01GM037408, R01GM048835)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- disease-associated mutations, missense mutations, protein structure, ligand binding sites, protein-protein interfaces, functional sites, 1000 Genomes Project, amino acid composition, human proteome
- MeSH terms
- Humans, Models, Molecular, Protein Conformation, Genetic Predisposition to Disease, Mutation, Missense, Proteome, Protein Interaction Domains and Motifs, Protein Interaction Maps
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