Avizemer, Ziv, Martí-Gómez, Carlos, Hoch, Shlomo Yakir, McCandlish, David M, Fleishman, Sarel J (April 2023) Evolutionary paths that link orthogonal pairs of binding proteins. Research Square. (Submitted)
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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 their affinity exceeds the threshold required for function 1-4 . Thus, homologous and high-specificity binding pairs bring to light an evolutionary conundrum: how does a new specificity evolve while maintaining the required affinity in each intermediate 5,6 ? Until now, a fully functional single-mutation path that connects two orthogonal pairs has only been described where the pairs were mutationally close enabling experimental enumeration of all intermediates 2 . We present an atomistic and graph-theoretical framework for discovering low molecular strain single-mutation paths that connect two extant pairs and apply it to two orthogonal bacterial colicin endonuclease-immunity pairs separated by 17 interface mutations 7 . We were not able to find a strain-free and functional path in the sequence space defined by the two extant pairs. By including mutations that bridge amino acids that cannot be exchanged through single-nucleotide mutations, we found a strain-free 19-mutation trajectory that is completely functional in vivo . Despite the long mutational trajectory, the specificity switch is remarkably abrupt, resulting from only one radical mutation on each partner. Each of the critical specificity-switch mutations increases fitness, demonstrating that functional divergence could be driven by positive Darwinian selection. These results reveal how even radical functional changes in an epistatic fitness landscape may evolve.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types |
| CSHL Authors: | |
| Communities: | CSHL labs > McCandlish lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 20 April 2023 |
| Date Deposited: | 28 Sep 2023 20:24 |
| Last Modified: | 20 Jun 2024 18:04 |
| PMCID: | PMC10153392 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41056 |
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