The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function.

Kamakshi Sureka*, Philip H. Choi, Mimi Precit, Matthieu Delince, Daniel A. Pensinger, TuAnh Ngoc Huynh, Ashley R. Jurado, Young Ah Goo, Martin Sadilek, Anthony T. Iavarone, John Demian Sauer, Liang Tong, Joshua J. Woodward

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Cyclic di-adenosine monophosphate (c-di-AMP) is a broadly conserved second messenger required for bacterial growth and infection. However, the molecular mechanisms of c-di-AMP signaling are still poorly understood. Using a chemical proteomics screen for c-di-AMP-interacting proteins in the pathogen Listeria monocytogenes, we identified several broadly conserved protein receptors, including the central metabolic enzyme pyruvate carboxylase (LmPC). Biochemical and crystallographic studies of the LmPC-c-di-AMP interaction revealed a previously unrecognized allosteric regulatory site 25 Å from the active site. Mutations in this site disrupted c-di-AMP binding and affected catalytic activity of LmPC as well as PC from pathogenic Enterococcus faecalis. C-di-AMP depletion resulted in altered metabolic activity in L. monocytogenes. Correction of this metabolic imbalance rescued bacterial growth, reduced bacterial lysis, and resulted in enhanced bacterial burdens during infection. These findings greatly expand the c-di-AMP signaling repertoire and reveal a central metabolic regulatory role for a cyclic dinucleotide.

Original languageEnglish (US)
Pages (from-to)1389-1401
Number of pages13
JournalCell
Volume158
Issue number6
DOIs
StatePublished - Sep 11 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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