Evolving new protein-protein interaction specificity through promiscuous intermediates.


Interacting proteins typically coevolve, and the identification of coevolving amino acids can pinpoint residues required for interaction specificity. This approach often assumes that an interface-disrupting mutation in one protein drives selection of a compensatory mutation in its partner during evolution. However, this model requires a non-functional intermediate state prior to the compensatory change. Alternatively, a mutation in one protein could first broaden its specificity, allowing changes in its partner, followed by a specificity-restricting mutation. Using bacterial toxin-antitoxin systems, we demonstrate the plausibility of this second, promiscuity-based model. By screening large libraries of interface mutants, we show that toxins and antitoxins with high specificity are frequently connected in sequence space to more promiscuous variants that can serve as intermediates during a reprogramming of interaction specificity. We propose that the abundance of promiscuous variants promotes the expansion and diversification of toxin-antitoxin systems and other paralogous protein families during evolution.

Submission Details

ID: dKxpexyu

Submitter: Connie Wang

Submission Date: Oct. 22, 2018, 12:44 p.m.

Version: 1

Publication Details
Aakre CD;Herrou J;Phung TN;Perchuk BS;Crosson S;Laub MT,Cell (2015) Evolving new protein-protein interaction specificity through promiscuous intermediates. PMID:26478181
Additional Information

Study Summary

Number of data points 9194
Proteins ParDE3
Unique complexes 9194
Assays/Quantities/Protocols Experimental Assay: fitness (log-fold expansion of each mutant relative to the population)
Libraries fitness

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)