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

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...

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Published in:Cell 2014-09, Vol.158 (6), p.1389-1401
Main Authors: Sureka, Kamakshi, Choi, Philip H, Precit, Mimi, Delince, Matthieu, Pensinger, Daniel A, Huynh, TuAnh Ngoc, Jurado, Ashley R, Goo, Young Ah, Sadilek, Martin, Iavarone, Anthony T, Sauer, John-Demian, Tong, Liang, Woodward, Joshua J
Format: Article
Language:English
Subjects:
Allosteric Regulation
Amino Acid Sequence
Animals
Bacteriolysis
Binding Sites
Crystallography, X-Ray
Dinucleoside Phosphates - metabolism
Host-Pathogen Interactions
Listeria monocytogenes - enzymology
Listeria monocytogenes - growth & development
Listeria monocytogenes - metabolism
Listeriosis - microbiology
Mice
Models, Molecular
Molecular Sequence Data
Pyruvate Carboxylase - chemistry
Pyruvate Carboxylase - metabolism
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2014.07.046