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

The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function
Published: 
Sep 2014
Publisher: 
Cell. 2014 Sep 11;158(6):1389-401. doi: 10.1016/j.cell.2014.07.046
Author: 
Joshua John Woodward, Ph.D.

Sureka K1, Choi PH2, Precit M1, Delince M3, Pensinger DA4, Huynh TN1, Jurado AR2, Goo YA5, Sadilek M6, Iavarone AT7, Sauer JD4, Tong L8, Woodward JJ9

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID: 25215494 [PubMed - indexed for MEDLINE]
PMCID:PMC4166403