Early divergence of translation initiation and elongation factors

Protein Sci. 2022 Sep;31(9):e4393. doi: 10.1002/pro.4393.


Protein translation is a foundational attribute of all living cells. The translation function carried out by the ribosome critically depends on an assortment of protein interaction partners, collectively referred to as the translation machinery. Various studies suggest that the diversification of the translation machinery occurred prior to the last universal common ancestor, yet it is unclear whether the predecessors of the extant translation machinery factors were functionally distinct from their modern counterparts. Here we reconstructed the shared ancestral trajectory and subsequent evolution of essential translation factor GTPases, elongation factor EF-Tu (aEF-1A/eEF-1A), and initiation factor IF2 (aIF5B/eIF5B). Based upon their similar functions and structural homologies, it has been proposed that EF-Tu and IF2 emerged from an ancient common ancestor. We generated the phylogenetic tree of IF2 and EF-Tu proteins and reconstructed ancestral sequences corresponding to the deepest nodes in their shared evolutionary history, including the last common IF2 and EF-Tu ancestor. By identifying the residue and domain substitutions, as well as structural changes along the phylogenetic history, we developed an evolutionary scenario for the origins, divergence and functional refinement of EF-Tu and IF2 proteins. Our analyses suggest that the common ancestor of IF2 and EF-Tu was an IF2-like GTPase protein. Given the central importance of the translation machinery to all cellular life, its earliest evolutionary constraints and trajectories are key to characterizing the universal constraints and capabilities of cellular evolution.

Keywords: LUCA; ancestral sequence reconstruction; elongation factor; initiation factor; translation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • GTP Phosphohydrolases / metabolism
  • Peptide Elongation Factor Tu* / genetics
  • Peptide Elongation Factor Tu* / metabolism
  • Phylogeny
  • Prokaryotic Initiation Factor-2* / genetics
  • Prokaryotic Initiation Factor-2* / metabolism
  • Proteins / metabolism
  • Ribosomes / metabolism


  • Prokaryotic Initiation Factor-2
  • Proteins
  • GTP Phosphohydrolases
  • Peptide Elongation Factor Tu