Recognizing self-versus nonself is a crucial step in the development of multicellularity. The social bacterium Myxococcus xanthus is a tractable model organism for studying this transition from single-cell to multicellular life. The polymorphic cell-surface receptor TraA directs cooperative behaviors toward kin. TraA is a highly specific receptor, capable of recognizing other TraA proteins with identical or nearly identical sequences by homotypic binding, but the molecular basis of this specificity remains poorly understood. Here, we generated a targeted TraA mutant library comprising thousands of variants with substitutions at 10 predicted specificity-determining residues. Screening revealed variants with altered recognition profiles, often resulting in promiscuous and/or heterotypic TraA-TraA interactions. We further identified key residues that govern specificity, as substitutions at these positions rewired recognition outcomes. Finally, we propose an evolutionary model in which new TraA specificities arise through promiscuous intermediate states shaped by reward-punishment dynamics. Together, these findings demonstrate the malleability of TraA specificity and provide molecular and evolutionary insight into social recognition.
Guo et al. (2026) studied this question.