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 and Christopher J. Squire ()
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Ghader Bashiri: The University of Auckland
Esther M. M. Bulloch: The University of Auckland
William R. Bramley: The University of Auckland
Madison Davidson: North Carolina State University
Stephanie M. Stuteley: The University of Auckland
Paul G. Young: The University of Auckland
Paul W. R. Harris: The University of Auckland
Muhammad S. H. Naqvi: The University of Auckland
Martin J. Middleditch: The University of Auckland
Michael Schmitz: The University of Auckland
Wei-Chen Chang: North Carolina State University
Edward N. Baker: The University of Auckland
Christopher J. Squire: The University of Auckland

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45632-1

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