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The Fic protein Doc uses an inverted substrate to phosphorylate and inactivate EF-Tu

Lookup NU author(s): Daniel Castro-Roa, Professor Nikolay ZenkinORCiD

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Abstract

Fic proteins are ubiquitous in all of the domains of life and have critical roles in multiple cellular processes through AMPylation of (transfer of AMP to) target proteins. Doc from the doc-phd toxin-antitoxin module is a member of the Fic family and inhibits bacterial translation by an unknown mechanism. Here we show that, in contrast to having AMPylating activity, Doc is a new type of kinase that inhibits bacterial translation by phosphorylating the conserved threonine (Thr382) of the translation elongation factor EF-Tu, rendering EF-Tu unable to bind aminoacylated tRNAs. We provide evidence that EF-Tu phosphorylation diverged from AMPylation by antiparallel binding of the NTP relative to the catalytic residues of the conserved Fic catalytic core of Doc. The results bring insights into the mechanism and role of phosphorylation of EF-Tu in bacterial physiology as well as represent an example of the catalytic plasticity of enzymes and a mechanism for the evolution of new enzymatic activities.

Publication metadata

Author(s): Castro-Roa D, Garcia-Pino A, De Gieter S, van Nuland NAJ, Loris R, Zenkin N

Publication type: Article

Publication status: Published

Journal: Nature Chemical Biology

Year: 2013

Volume: 9

Issue: 12

Pages: 811-817

Print publication date: 01/12/2013

Online publication date: 20/10/2013

Acceptance date: 06/09/2013

ISSN (print): 1552-4450

ISSN (electronic): 1552-4469

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nchembio.1364

DOI: 10.1038/nchembio.1364

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