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PDBsum entry 4s1c
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References listed in PDB file
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Key reference
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Title
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An hd-Domain phosphodiesterase mediates cooperative hydrolysis of c-Di-Amp to affect bacterial growth and virulence.
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Authors
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T.N.Huynh,
S.Luo,
D.Pensinger,
J.D.Sauer,
L.Tong,
J.J.Woodward.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
E747.
[DOI no: ]
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PubMed id
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Abstract
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The nucleotide cyclic di-3',5'- adenosine monophosphate (c-di-AMP) was recently
identified as an essential and widespread second messenger in bacterial
signaling. Among c-di-AMP-producing bacteria, altered nucleotide levels result
in several physiological defects and attenuated virulence. Thus, a detailed
molecular understanding of c-di-AMP metabolism is of both fundamental and
practical interest. Currently, c-di-AMP degradation is recognized solely among
DHH-DHHA1 domain-containing phosphodiesterases. Using chemical proteomics, we
identified the Listeria monocytogenes protein PgpH as a molecular target of
c-di-AMP. Biochemical and structural studies revealed that the PgpH His-Asp (HD)
domain bound c-di-AMP with high affinity and specifically hydrolyzed this
nucleotide to 5'-pApA. PgpH hydrolysis activity was inhibited by ppGpp,
indicating a cross-talk between c-di-AMP signaling and the stringent response.
Genetic analyses supported coordinated regulation of c-di-AMP levels in and out
of the host. Intriguingly, a L. monocytogenes mutant that lacks c-di-AMP
phosphodiesterases exhibited elevated c-di-AMP levels, hyperinduced a host
type-I IFN response, and was significantly attenuated for infection.
Furthermore, PgpH homologs, which belong to the 7TMR-HD family, are widespread
among hundreds of c-di-AMP synthesizing microorganisms. Thus, PgpH represents a
broadly conserved class of c-di-AMP phosphodiesterase with possibly other
physiological functions in this crucial signaling network.
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