Widespread macromolecular interaction perturbations in human genetic disorders
Open accessAbstract
How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.
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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 [43]
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Kadam, V., Bhargav, P., & Mukherjee, A. (2026) · Journal of Chemical Sciences · doi:10.1007/s12039-025-02459-7
- Authors
- Sahni, N., Yi, S., Taipale, M., Fuxman Bass, J. I., Coulombe-Huntington, J., Yang, F., Peng, J., Weile, J., Karras, G. I., Wang, Y., Kovács, I. A., Kamburov, A., Krykbaeva, I., Lam, M. H., Tucker, G., Khurana, V., Sharma, A., Liu, Y.-Y., Yachie, N., Zhong, Q., Shen, Y., Palagi, A., San-Miguel, A., Fan, C., Balcha, D., Dricot, A., Jordan, D. M., Walsh, J. M., Shah, A. A., Yang, X., Stoyanova, A. K., Leighton, A., Calderwood, M. A., Jacob, Y., Cusick, M. E., Salehi-Ashtiani, K., Whitesell, L. J., Sunyaev, S., Berger, B., Barabási, A.-L., Charloteaux, B., Hill, D. E., Hao, T., Roth, F. P., Xia, Y., Walhout, A. J. M., Lindquist, S., & Vidal, M.
- Affiliations
- Harvard University (US)
- Whitehead Institute for Biomedical Research (US)
- Mount Sinai Hospital (CA)
- Massachusetts Institute of Technology (US)
- University of Toronto (CA)
- Northeastern University (US)
- Brigham and Women's Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- Howard Hughes Medical Institute (US)
- Broad Institute (US)
- MIT Computer Science and Artificial Intelligence Laboratory (US)
- Canadian Institute for Advanced Research (CA)
- Dana-Farber Cancer Institute (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Lindquist, Susan
- Vidal, Marc
- ORCID
- Sahni, Nidhi
- Yi, Song
- Taipale, Mikko
- Yang, Fan
- Peng, Jian
- Weile, Jochen
- Karras, Georgios I.
- Wang, Yang
- Kamburov, Atanas
- Krykbaeva, Irina
- Lam, Mandy H.
- Khurana, Vikram
- Sharma, Amitabh
- Liu, Yang-Yu
- Yachie, Nozomu
- Zhong, Quan
- Jordan, Daniel M.
- Shah, Akash A.
- Yang, Xinping
- Stoyanova, Ani K.
- Calderwood, Michael A.
- Jacob, Yves
- Whitesell, Luke J.
- Sunyaev, Shamil
- Berger, Bonnie
- Hill, David E.
- Hao, Tong
- Roth, Frederick P.
- Xia, Yu
- Walhout, Albertha J.M.
- Vidal, Marc
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 161
- Issue
- 3
- Pages
- 647-660
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4441215
- OpenAlex
- W2119097398
- Cited by
- 594
- References
- 71
- Citations by year
- 2026: 49 · 2025: 46 · 2024: 63 · 2023: 43 · 2022: 45 · 2021: 54 · 2020: 61 · 2019: 50 · 2018: 66 · 2017: 40 · 2016: 52 · 2015: 24 · 2014: 1
- FWCI
- 41.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Open Repository and Bibliography (University of Liège) (submittedVersion)
- PMC
- Funders
- Howard Hughes Medical Institute
- Dana-Farber Cancer Institute
- National Human Genome Research Institute (R01HG001715, RC4HG006066, U41HG001715, P50HG004233)
- National Institute of General Medical Sciences (R01GM082971, R01GM081871, GM082971)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- disease-associated mutations, missense mutations, protein-protein interaction, protein folding, protein stability, transcription factor-DNA binding, monogenic disorders, genotype-phenotype correlation
- MeSH terms
- Disease, DNA-Binding Proteins, Humans, Proteins, Open Reading Frames, Protein Folding, Mutation, Missense, Genome-Wide Association Study, Protein Stability, Protein Interaction Maps
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