Avizemer, Ziv, Martí-Gómez, Carlos, Hoch, Shlomo Yakir, McCandlish, David M, Fleishman, Sarel J (April 2025) Evolutionary paths that link orthogonal pairs of binding proteins. Cell Systems, 32 (12). p. 101262. ISSN 0961-8368 (Public Dataset)
Abstract
Some protein-binding pairs exhibit extreme specificities that functionally insulate them from homologs. Such pairs evolve mostly by accumulating single-point mutations, and mutants are selected if they exhibit sufficient affinity. Until now, finding a fully functional single-mutation path connecting orthogonal pairs could only be achieved by full enumeration of intermediates and was restricted to pairs that were mutationally close. We present a computational framework for discovering single-mutation paths with low molecular strain and apply it to two orthogonal bacterial endonuclease-immunity pairs separated by 17 interfacial mutations. By including mutations that bridge identities that could not be exchanged by single-nucleotide mutations, we discovered a strain-free 19-mutation path that was fully functional in vivo. The change in binding preference occurred remarkably abruptly, resulting from only one radical mutation in each partner. Furthermore, each of the specificity-switch mutations increased fitness, demonstrating that functional divergence could be driven by positive Darwinian selection.
| Item Type: | Paper |
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| Subjects: | bioinformatics bioinformatics > genomics and proteomics > design bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > design > protein design bioinformatics > quantitative biology bioinformatics > quantitative biology > quantitative genetics > quantitative epistasis bioinformatics > quantitative biology > quantitative genetics |
| CSHL Authors: | |
| Communities: | CSHL labs > McCandlish lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 10 April 2025 |
| Date Deposited: | 14 Apr 2025 12:36 |
| Last Modified: | 14 Apr 2025 12:36 |
| Related URLs: | |
| Dataset ID: |
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| URI: | https://repository.cshl.edu/id/eprint/41848 |
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