Evolutionary extensions of IF2 couple translation initiation to bacterial stress adaptation

Ancient protein cores are deeply conserved across the tree of life, yet lineage-specific functional innovation frequently relies on terminal extensions. How these structurally dynamic regions drive functional divergence remains unclear. Here, we investigated terminal extensions in translation initiation factor 2 (IF2), an essential component of the translation machinery. Comparative analysis of IF2 homologs across the tree of life reveals extensive diversification of both N- and C- terminal regions into seven distinct structural architectures, enriched in intrinsically disordered and phase-separation–promoting residues. In Escherichia coli, shortening the native N-terminal extension selectively impairs growth under temperature and pH stress. Conversely, appending divergent C-terminal extensions from different organisms to the E. coli IF2 demonstrates a conserved stress-responsive role in adaptation to temperature and anaerobiosis. Overall, terminal extensions expand IF2’s functional repertoire by coupling translation initiation to stress adaptation, providing a general mechanism by which evolutionary expansion confers regulatory flexibility without altering essential ancestral functions. Translation initiation factor 2 (IF2) is a universally conserved component of the protein synthesis machinery. Here, Fer et al. show that IF2 terminal extensions couple translation initiation to stress adaptation, highlighting a mechanism by which evolutionary expansion of core proteins enables regulatory flexibility in changing environments.