TY - JOUR
T1 - The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function.
AU - Sureka, Kamakshi
AU - Choi, Philip H.
AU - Precit, Mimi
AU - Delince, Matthieu
AU - Pensinger, Daniel A.
AU - Huynh, Tu Anh Ngoc
AU - Jurado, Ashley R.
AU - Goo, Young Ah
AU - Sadilek, Martin
AU - Iavarone, Anthony T.
AU - Sauer, John Demian
AU - Tong, Liang
AU - Woodward, Joshua J.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84908079796&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.07.046
DO - 10.1016/j.cell.2014.07.046
M3 - Article
C2 - 25215494
AN - SCOPUS:84908079796
SN - 0092-8674
VL - 158
SP - 1389
EP - 1401
JO - Cell
JF - Cell
IS - 6
ER -