Functional analysis of c-di-AMP phosphodiesterase, GdpP, in Streptococcus suis serotype 2

Du, Bin; Ji, Wenhui; An, Huiting; Shi, Yiting; Huang, Qingqing; Cheng, Yuqiang; Fu, Qiang; Wang, Hengan; Yan, Yaxian; Sun, Jianhe

doi:10.1016/j.micres.2014.01.002

Cited by 60 publications

(78 citation statements)

References 36 publications

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“…MsPDE is an ortholog of B. subtilis YybT. Comparing with YybT, which contains an extra transmembrane domain and a modified GGDEF domain involved in signal sensing, MsPDE only contains DHH-DHHA1 domain which is conserved in all the reported c-di-AMP specific-PDEs 7, 11, 33, 38-40. Recently, a structural study on PDE revealed the molecular mechanism of its flexibility on substrates recognition 27.…”

Section: Discussionmentioning

confidence: 99%

“…All the reported c-di-AMP-specific PDEs belong to DHH family 7, 11, 33, 38-40, and the function of DHH family proteins is versatile and various. B. subtilis possesses four DHH family proteins: BsYybT, BsYtqI, BsRecJ and BsPPase.…”

Section: Discussionmentioning

confidence: 99%

“…The reported PDEs belong to three different families, one is GdpP protein family (GGDEF domain protein-containing phosphodiesterase) which consists of an N-terminal signal regulatory module linked to a degenerate GGDEF domain and a C-terminal DHH-DHHA1 domain module, an other family only contains a DHH-DHHA1 domain, and the third is 7TMR family which contains a HD domian 7, 11, 15, 33, 38-40. Accession numbers: PgpH- L. monocytogenes : 4S1B_A; GdpP- L. lactis : CAL98387; GdpP- S. aureus : YP_498622; GdpP- S. pyogenes : NP_270093; GdpP- S. suis : ABP93318; PdeA- L. monocytogenes : CAC98267; YybT- B. subtilis : NP_391931; Pde1- S. pneumonia : ABJ55207; PDE- M. smegmatis : YP_886967; PDE- M. tuberculosis : P71615; Dhhp- B. burgdorferi : NP_212753; Pde2- S. pneumonia : SPD_1153.…”

Section: Figurementioning

confidence: 99%

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Functional Analysis of a c-di-AMP-specific Phosphodiesterase MsPDE from Mycobacterium smegmatis

Tang¹,

Luo²,

Cao³

et al. 2015

Int. J. Biol. Sci.

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Cyclic di‑AMP (c-di-AMP) is a second signaling molecule involved in the regulation of bacterial physiological processes and interaction between pathogen and host. However, the regulatory network mediated by c-di-AMP in Mycobacterium remains obscure. In M. smegmatis, a diadenylate cyclase (DAC) was reported recently, but there is still no investigation on c-di-AMP phosphodiesterase (PDE). Here, we provide a systematic study on signaling mechanism of c-di-AMP PDE in M. smegmatis. Based on our enzymatic analysis, MsPDE (MSMEG_2630), which contained a DHH-DHHA1 domain, displayed a 200-fold higher hydrolytic efficiency (kcat/Km) to c-di-AMP than to c-di-GMP. MsPDE was capable of converting c-di-AMP to pApA and AMP, and hydrolyzing pApA to AMP. Site-directed mutations in DHH and DHHA1 revealed that DHH domain was critical for the phosphodiesterase activity. To explore the regulatory role of c-di-AMP in vivo, we constructed the mspde mutant (Δmspde) and found that deficiency of MsPDE significantly enhanced intracellular C12-C20 fatty acid accumulation. Deficiency of DAC in many bacteria results in cell death. However, we acquired the M. smegmatis strain with DAC gene disrupted (ΔmsdisA) by homologous recombination approach. Deletion of msdisA reduced bacterial C12-C20 fatty acids production but scarcely affected bacterial survival. We also provided evidences that superfluous c-di-AMP in M. smegmatis could lead to abnormal colonial morphology. Collectively, our results indicate that MsPDE is a functional c-di-AMP-specific phosphodiesterase both in vitro and in vivo. Our study also expands the regulatory network mediated by c-di-AMP in M. smegmatis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Functional Analysis of a c-di-AMP-specific Phosphodiesterase MsPDE from Mycobacterium smegmatis

Tang¹,

Luo²,

Cao³

et al. 2015

Int. J. Biol. Sci.

View full text Add to dashboard Cite

show abstract

“…This would be consistent with the observation that the L. monocytogenes homolog is more active in host cells than in broth growth. In addition, the S. suis gdpP mutant has reduced hemolytic activity on erythrocytes [17], and the L. lactis gdpP mutant is highly sensitive to heme stress [16]. Beyond heme, PAS domains have been implicated as allosteric receptors of a broad array of small molecule signals.…”

Section: Introductionmentioning

confidence: 99%

Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm

Huynh

Woodward

2016

Current Opinion in Microbiology

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“…2–4 One such molecule, cyclic diadenosine monophosphate (c-di-AMP), has recently been identified as a second messenger in a wide variety of bacteria. 5,6 C-di-AMP signaling has been implicated in a diverse set of processes including sporulation 7 , peptidoglycan homeostasis 8,9 , cell size 8,10 , biofilm formation 8,10,11 , virulence 10,12–16 , and cell viability. 8,9,15–21 In addition, c-di-AMP has been shown to activate an innate immune response via the human host proteins STING and DDX41.…”

Section: Introductionmentioning

confidence: 99%

Nuclease-Resistant c-di-AMP Derivatives That Differentially Recognize RNA and Protein Receptors

Meehan¹,

Torgerson²,

Gaffney

et al. 2016

Biochemistry

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The ability of bacteria to sense environmental cues and adapt is essential for their survival. The use of second-messenger signaling molecules to translate these cues into a physiological response is a common mechanism employed by bacteria. The second messenger 3’-5’-cyclic diadenosine monophosphate (c-di-AMP) has been linked to a diverse set of biological processes involved in maintaining cell viability and homeostasis, as well as pathogenicity. A complex network of both protein and RNA receptors inside the cell activate specific pathways and mediate phenotypic outputs in response to c-di-AMP. Structural analysis of these RNA and protein receptors has revealed the different recognition elements employed by these effectors to bind the same small molecule. Herein, using a series of c-di-AMP analogs, we probed the interactions made with a riboswitch and a phosphodiesterase protein to identify the features important for c-di-AMP binding and recognition. We found that the ydaO riboswitch binds c-di-AMP in two discrete sites with near identical affinity and a Hill coefficient of 1.6. The ydaO riboswitch distinguishes between c-di-AMP and structurally related second messengers by discriminating against an amine at the C2 position, more than a carbonyl at the C6 position. We also identified phosphate-modified analogs that bind both the ydaO RNA and GdpP protein with high affinity, while symmetrically-modified ribose analogs exhibited a substantial decrease in ydaO affinity, but retained high affinity for GdpP. These ligand modifications resulted in increased resistance to enzyme-catalyzed hydrolysis by the GdpP enzyme. Together, these data suggest that these c-di-AMP analogs could be useful as chemical tools to specifically target subsections of the second-messenger signaling pathways.

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Functional analysis of c-di-AMP phosphodiesterase, GdpP, in Streptococcus suis serotype 2

Cited by 60 publications

References 36 publications

Functional Analysis of a c-di-AMP-specific Phosphodiesterase MsPDE from Mycobacterium smegmatis

Functional Analysis of a c-di-AMP-specific Phosphodiesterase MsPDE from Mycobacterium smegmatis

Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm

Nuclease-Resistant c-di-AMP Derivatives That Differentially Recognize RNA and Protein Receptors

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