An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence

Huynh, TuAnh Ngoc; Luo, Shukun; Pensinger, Daniel A.; Sauer, John-Demian; Tong, Liang; Woodward, Joshua J.

doi:10.1073/pnas.1416485112

Cited by 175 publications

(264 citation statements)

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“…c-di-GMP is down-regulated by EAL domain and HD-GYP domain, resulting in 5Ј-pGpG and GMP, respectively (6,39), whereas c-di-AMP is broken down by stand-alone DHH-DHHA1 domain and membrane-bound DHH-DHHA1, as well as HD domain to AMP and 5Ј-pApA, respectively (16,18,40). M. tuberculosis does not have HD-GYP domain protein and seems lack an essential link in c-di-GMP metabolism (41).…”

Section: The Oligomeric State Of C-di-nmps Affects Rv2837cmentioning

confidence: 99%

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Structural and Biochemical Insight into the Mechanism of Rv2837c from Mycobacterium tuberculosis as a c-di-NMP Phosphodiesterase

Wang

Liu

et al. 2016

Journal of Biological Chemistry

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The intracellular infections of Mycobacterium tuberculosis, which is the causative agent of tuberculosis, are regulated by many cyclic dinucleotide signaling. Rv2837c from M. tuberculosis is a soluble, stand-alone DHH-DHHA1 domain phosphodiesterase that down-regulates c-di-AMP through catalytic degradation and plays an important role in M. tuberculosis infections. Here, we report the crystal structure of Rv2837c (2.0 Å ), and its complex with hydrolysis intermediate 5-pApA (2.35 Å ). Our structures indicate that both DHH and DHHA1 domains are essential for c-di-AMP degradation. Further structural analysis shows that Rv2837c does not distinguish adenine from guanine, which explains why Rv2837c hydrolyzes all linear dinucleotides with almost the same efficiency. We observed that Rv2837c degraded other c-di-NMPs at a lower rate than it did on c-di-AMP. Nevertheless, our data also showed that Rv2837c significantly decreases concentrations of both c-di-AMP and c-di-GMP in vivo. Our results suggest that beside its major role in c-di-AMP degradation Rv2837c could also regulate c-di-GMP signaling pathways in bacterial cell.

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Section: The Oligomeric State Of C-di-nmps Affects Rv2837cmentioning

confidence: 99%

“…One group is GdpP-like protein family, which usually contains a tandem PAS domain, a degenerate GGDEF domain, and a catalytic DHH-DHHA1 domain (19). The other group is recently discovered PgpH protein family, which contains an extracellular 7TM receptor-like domain and a cytoplasmic HD domain (18). They all hydrolyze c-di-AMP into linear dinucleotide 5Ј-pApA.…”

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confidence: 99%

Structural and Biochemical Insight into the Mechanism of Rv2837c from Mycobacterium tuberculosis as a c-di-NMP Phosphodiesterase

Wang

Liu

et al. 2016

Journal of Biological Chemistry

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“…Recently, PgpH was identified as a second c-di-AMP-specific phosphodiesterase in L. monocytogenes (22). This prompted us to test whether the corresponding protein of B. subtilis (YqfF; here renamed PgpH) might also have this function and how the two potential phosphodiesterases, GdpP and PgpH, act together to control the intracellular c-di-AMP concentration.…”

Section: Figmentioning

confidence: 99%

“…The second class of phosphodiesterases contains a His-Asp motif in the active center (HD domain). The first, and so far only, representative of this family, PgpH, was only recently discovered and characterized in L. monocytogenes (22). PgpH has a homolog in B. subtilis (YqfF; here renamed PgpH) but is absent from S. aureus.…”

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confidence: 99%

An Essential Poison: Synthesis and Degradation of Cyclic Di-AMP in Bacillus subtilis

et al. 2015

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Gram-positive bacteria synthesize the second messenger cyclic di-AMP (c-di-AMP) to control cell wall and potassium homeostasis and to secure the integrity of their DNA. In the firmicutes, c-di-AMP is essential for growth. The model organism Bacillus subtilis encodes three diadenylate cyclases and two potential phosphodiesterases to produce and degrade c-di-AMP, respectively. Among the three cyclases, CdaA is conserved in nearly all firmicutes, and this enzyme seems to be responsible for the c-di-AMP that is required for cell wall homeostasis. Here, we demonstrate that CdaA localizes to the membrane and forms a complex with the regulatory protein CdaR and the glucosamine-6-phosphate mutase GlmM. Interestingly, cdaA, cdaR, and glmM form a gene cluster that is conserved throughout the firmicutes. This conserved arrangement and the observed interaction between the three proteins suggest a functional relationship. Our data suggest that GlmM and GlmS are involved in the control of c-di-AMP synthesis. These enzymes convert glutamine and fructose-6-phosphate to glutamate and glucosamine-1-phosphate. c-di-AMP synthesis is enhanced if the cells are grown in the presence of glutamate compared to that in glutamine-grown cells. Thus, the quality of the nitrogen source is an important signal for c-di-AMP production. In the analysis of c-di-AMP-degrading phosphodiesterases, we observed that both phosphodiesterases, GdpP and PgpH (previously known as YqfF), contribute to the degradation of the second messenger. Accumulation of c-di-AMP in a gdpP pgpH double mutant is toxic for the cells, and the cells respond to this accumulation by inactivation of the diadenylate cyclase CdaA. IMPORTANCEBacteria use second messengers for signal transduction. Cyclic di-AMP (c-di-AMP) is the only second messenger known so far that is essential for a large group of bacteria. We have studied the regulation of c-di-AMP synthesis and the role of the phosphodiesterases that degrade this second messenger. c-di-AMP synthesis strongly depends on the nitrogen source: glutamategrown cells produce more c-di-AMP than glutamine-grown cells. The accumulation of c-di-AMP in a strain lacking both phosphodiesterases is toxic and results in inactivation of the diadenylate cyclase CdaA. Our results suggest that CdaA is the critical diadenylate cyclase that produces the c-di-AMP that is both essential and toxic upon accumulation. In order to process environmental information in the cell, many organisms are capable of synthesizing so-called second messengers. These small molecules are formed in response to primary signals and perceived by cellular targets. Bacteria often use specific nucleotides as second messengers. These nucleotides include cyclic mononucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), as well as cyclic dinucleotides, such as cyclic di-AMP (c-di-AMP), cyclic di-GMP (c-di-GMP), and (p) ppGpp (1-3).The investigation of c-di-AMP-mediated signaling has recently attracted much attention (2). This molecule is formed by many bacteria a...

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“…To date, several phosphodiesterases (PDEs) have been found to hydrolyze c-di-GMP (EAL or HD-GYP domain-containing enzymes) [1] and c-di-AMP (DHH-DHHA or HD domain-containing enzymes) [2,10] (Figure 1). In addition, recent research reported that ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) is the dominant 2′3′-cGAMP hydrolyzing enzyme in mammalian cells [11] (Figure 1).…”

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confidence: 99%

V-cGAPs: attenuators of 3′3′-cGAMP signaling

Gao

Patel

2015

Cell Res

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An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence

Cited by 175 publications

References 51 publications

Structural and Biochemical Insight into the Mechanism of Rv2837c from Mycobacterium tuberculosis as a c-di-NMP Phosphodiesterase

Structural and Biochemical Insight into the Mechanism of Rv2837c from Mycobacterium tuberculosis as a c-di-NMP Phosphodiesterase

An Essential Poison: Synthesis and Degradation of Cyclic Di-AMP in Bacillus subtilis

V-cGAPs: attenuators of 3′3′-cGAMP signaling

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