Evolutionary paths that link orthogonal pairs of binding proteins.

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. (Submitted)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/37131620
DOI: 10.21203/rs.3.rs-2836905/v1


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: 28 Sep 2023 20:24
PMCID: PMC10153392
Related URLs:
URI: https://repository.cshl.edu/id/eprint/41056

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