Co-evolution of interacting proteins through non-contacting and non-specific mutations
Name
nihms-1776305.pdf
Description
Accepted version
Size
5.63 MB
Format
Adobe PDF
Checksum (MD5)
8b22fd1b3ae44a8b1212cff60c8aaedc
Author(s)
Ding, David
Green, Anna G
Wang, Boyuan
Lite, Thuy-Lan Vo
Weinstein, Eli N
Marks, Debora S
Laub, Michael T
Date Issued
2022
Journal
Nature Ecology & Evolution
Publisher
Springer Science and Business Media LLC
Citation
Ding, David, Green, Anna G, Wang, Boyuan, Lite, Thuy-Lan Vo, Weinstein, Eli N et al. 2022. "Co-evolution of interacting proteins through non-contacting and non-specific mutations." Nature Ecology & Evolution, 6 (5).
Version
Author's final manuscript
Abstract
Proteins often accumulate neutral mutations that do not affect current functions but can profoundly influence future mutational possibilities and functions. Understanding such hidden potential has major implications for protein design and evolutionary forecasting but has been limited by a lack of systematic efforts to identify potentiating mutations. Here, through the comprehensive analysis of a bacterial toxin-antitoxin system, we identified all possible single substitutions in the toxin that enable it to tolerate otherwise interface-disrupting mutations in its antitoxin. Strikingly, the majority of enabling mutations in the toxin do not contact and promote tolerance non-specifically to many different antitoxin mutations, despite covariation in homologues occurring primarily between specific pairs of contacting residues across the interface. In addition, the enabling mutations we identified expand future mutational paths that both maintain old toxin-antitoxin interactions and form new ones. These non-specific mutations are missed by widely used covariation and machine learning methods. Identifying such enabling mutations will be critical for ensuring continued binding of therapeutically relevant proteins, such as antibodies, aimed at evolving targets.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/S41559-022-01688-0
