title: Evolving new protein-protein interaction specificity through promiscuous intermediates.
abstract: 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.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Aakre
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Herrou
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Tuyen N
authors.initials: TN
authors.lastname: Phung
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Barrett S
authors.initials: BS
authors.lastname: Perchuk
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Crosson
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: laub@mit.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Laub
mesh_terms: D000595:Amino Acid Sequence; D000992:Antitoxins / Q000737:chemistry / Q000378:metabolism; D001419:Bacteria / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D019143:Evolution, Molecular; D059128:Mesorhizobium / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D060066:Protein Interaction Maps
chemical_list: D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004268:DNA-Binding Proteins; C078613:parD protein, Bacteria