Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders
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Berger_Widespread macromolecular.pdf
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Author(s)
Peng, Jian
Tucker, George Jay
Leighton, Alexander T.
Berger Leighton, Bonnie
Date Issued
April 2015
Journal
Cell
Publisher
Elsevier
Citation
Sahni, Nidhi, Song Yi, Mikko Taipale, Juan I. Fuxman Bass, Jasmin Coulombe-Huntington, Fan Yang, Jian Peng, et al. “Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders.” Cell 161, no. 3 (April 2015): 647–660.
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Department of Mathematics
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cell.2015.04.013
