Co-evolution of interacting proteins through non-contacting and non-specific mutations
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 sy...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2022
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| Online Access: | https://hdl.handle.net/1721.1/146870 |
| _version_ | 1826188807122190336 |
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| author | Ding, David Green, Anna G Wang, Boyuan Lite, Thuy-Lan Vo Weinstein, Eli N Marks, Debora S Laub, Michael T |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Ding, David Green, Anna G Wang, Boyuan Lite, Thuy-Lan Vo Weinstein, Eli N Marks, Debora S Laub, Michael T |
| author_sort | Ding, David |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:05:20Z |
| format | Article |
| id | mit-1721.1/146870 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:05:20Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1468702022-12-14T03:47:49Z Co-evolution of interacting proteins through non-contacting and non-specific mutations Ding, David Green, Anna G Wang, Boyuan Lite, Thuy-Lan Vo Weinstein, Eli N Marks, Debora S Laub, Michael T Massachusetts Institute of Technology. Department of Biology 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. 2022-12-13T20:02:09Z 2022-12-13T20:02:09Z 2022 2022-12-13T19:26:19Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146870 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). en 10.1038/S41559-022-01688-0 Nature Ecology & Evolution Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Ding, David Green, Anna G Wang, Boyuan Lite, Thuy-Lan Vo Weinstein, Eli N Marks, Debora S Laub, Michael T Co-evolution of interacting proteins through non-contacting and non-specific mutations |
| title | Co-evolution of interacting proteins through non-contacting and non-specific mutations |
| title_full | Co-evolution of interacting proteins through non-contacting and non-specific mutations |
| title_fullStr | Co-evolution of interacting proteins through non-contacting and non-specific mutations |
| title_full_unstemmed | Co-evolution of interacting proteins through non-contacting and non-specific mutations |
| title_short | Co-evolution of interacting proteins through non-contacting and non-specific mutations |
| title_sort | co evolution of interacting proteins through non contacting and non specific mutations |
| url | https://hdl.handle.net/1721.1/146870 |
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