Nature Communications (Feb 2024)

Poly-γ-glutamylation of biomolecules

  • Ghader Bashiri,
  • Esther M. M. Bulloch,
  • William R. Bramley,
  • Madison Davidson,
  • Stephanie M. Stuteley,
  • Paul G. Young,
  • Paul W. R. Harris,
  • Muhammad S. H. Naqvi,
  • Martin J. Middleditch,
  • Michael Schmitz,
  • Wei-Chen Chang,
  • Edward N. Baker,
  • Christopher J. Squire

DOI
https://doi.org/10.1038/s41467-024-45632-1
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 11

Abstract

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Abstract Poly-γ-glutamate tails are a distinctive feature of archaeal, bacterial, and eukaryotic cofactors, including the folates and F420. Despite decades of research, key mechanistic questions remain as to how enzymes successively add glutamates to poly-γ-glutamate chains while maintaining cofactor specificity. Here, we show how poly-γ-glutamylation of folate and F420 by folylpolyglutamate synthases and γ-glutamyl ligases, non-homologous enzymes, occurs via processive addition of L-glutamate onto growing γ-glutamyl chain termini. We further reveal structural snapshots of the archaeal γ-glutamyl ligase (CofE) in action, crucially including a bulged-chain product that shows how the cofactor is retained while successive glutamates are added to the chain terminus. This bulging substrate model of processive poly-γ-glutamylation by terminal extension is arguably ubiquitous in such biopolymerisation reactions, including addition to folates, and demonstrates convergent evolution in diverse species from archaea to humans.