Evolving new protein-protein interaction specificity through promiscuous intermediates

By Christopher D. Aakre, J. Herrou, T. Phung, Barrett S. Perchuk, S. Crosson, M. Laub. 2015

196 citations recorded by the source corpus.

Summary 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.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

Connecting the Sequence-Space of Bacterial Signaling Proteins to Phenotypes Using Coevolutionary Landscapes (2016, background): “One potential example is the toxinantitoxin protein pairs in bacteria, which was the focus of recent experimental work (Aakre et al. 2015) elucidating the determinants of interaction specificity.”
The genetic landscape of a physical interaction (2018, background): “However, to date, the effects of mutations on PPIs have only been quantified for deep mutant libraries of one protein in combination with a small number of targeted mutants in a physical interaction partner (Aakre et al., 2015; Araya et al., 2012; Raman et al., 2016).”
Predicting evolution (2017, background): “Compensatory evolution can be quite rapid 88 , and the order of serpentine steps can be reversed: a change in a conserved trait facilitates a subsequent adaptive step 59,89 .”
Epistasis in protein evolution (2016, background): “Some studies set a threshold to distinguish between putatively functional and nonfunctional (or fit and unfit) genotypes and, in turn, to classify evolutionary pathways through sequence space as passable or not.(36,60,72) Imposing this kind of nonlinearity will necessarily lead to apparent epistasis”