Identification and characterization of phosphodiesterases that specifically degrade 3′3′-cyclic GMP-AMP

Gao, Juyi; Tao, Junhua; Liang, Weili; Zhao, Meng; Du, Xiaoxia; Cui, Shan; Duan, Haifeng; Kan, Biao; Su, Xiao‐Dong; Jiang, Zhengfan

doi:10.1038/cr.2015.40

Cited by 79 publications

(93 citation statements)

References 39 publications

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“…Our results reveal that the large abundance and redundancy of GGDEF genes in bacterial genomes have allowed this enzyme family to diverge and evolve toward new synthase activity; the distribution of HD-GYP and EAL phosphodiesterase domains also are expanded in Deltaproteobacteria (9), and at least one variant HD-GYP domain has been shown to degrade cAG (34). Besides synthesizing cAG, we also showed that GGDEF domains can make cdiA, an activity that had been speculated (43), but only now proven.…”

Section: Whereas Previous Ggdef Enzymes Were Uniformly Assigned As Dgmentioning

confidence: 94%

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Hybrid promiscuous (Hypr) GGDEF enzymes produce cyclic AMP-GMP (3′, 3′-cGAMP)

Hallberg

Wang

Wright

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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Over 30 years ago, GGDEF domain-containing enzymes were shown to be diguanylate cyclases that produce cyclic di-GMP (cdiG), a second messenger that modulates the key bacterial lifestyle transition from a motile to sessile biofilm-forming state. Since then, the ubiquity of genes encoding GGDEF proteins in bacterial genomes has established the dominance of cdiG signaling in bacteria. However, the observation that proteobacteria encode a large number of GGDEF proteins, nearing 1% of coding sequences in some cases, raises the question of why bacteria need so many GGDEF enzymes. In this study, we reveal that a subfamily of GGDEF enzymes synthesizes the asymmetric signaling molecule cyclic AMP-GMP (cAG or 3′, 3′-cGAMP). This discovery is unexpected because GGDEF enzymes function as symmetric homodimers, with each monomer binding to one substrate NTP. Detailed analysis of the enzyme from Geobacter sulfurreducens showed it is a dinucleotide cyclase capable of switching the major cyclic dinucleotide (CDN) produced based on ATP-to-GTP ratios. We then establish through bioinformatics and activity assays that hybrid CDN-producing and promiscuous substrate-binding (Hypr) GGDEF enzymes are found in other deltaproteobacteria. Finally, we validated the predictive power of our analysis by showing that cAG is present in surface-grown Myxococcus xanthus. This study reveals that GGDEF enzymes make alternative cyclic dinucleotides to cdiG and expands the role of this widely distributed enzyme family to include regulation of cAG signaling.bacterial signaling | surface sensing | second messengers | cyclic dinucleotides | fluorescent biosensor

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Section: Whereas Previous Ggdef Enzymes Were Uniformly Assigned As Dgmentioning

confidence: 94%

“…The enzyme TBD1265, for instance, is a canonical EAL domain-containing phosphodiesterase that is 33-fold more selective for cdiG over cAG, with no activity toward cdiA hydrolysis (33). Furthermore, of the 28 HD-GYP and EAL proteins in V. cholera El Tor, only three HD-GYP enzymes showed cleavage activity for cAG (34).…”

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confidence: 99%

Hybrid promiscuous (Hypr) GGDEF enzymes produce cyclic AMP-GMP (3′, 3′-cGAMP)

Hallberg

Wang

Wright

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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“…The 3=3=-cyclic GMP-AMP molecule was discovered in Vibrio cholerae as a regulator of chemotaxis and of factors contributing to colonization of the intestine (86). A screen of potential phosphodiesterases for 3=3=-cyclic GMP-AMP from V. cholerae identified three HD-GYP domain proteins, VCA0210, VCA0681, and VCA0931, which were capable of hydrolysis of the cyclic dinucleotide into 5=-pApG, with VCA0681 having an additional 5=-nucleotidase activity to generate 5=-ApG (87). The nucleotidase and phosphodiesterase activities were associated with the HD and HD-GYP domains, respectively, which are present in tandem (87).…”

Section: Further Substrates For Hd-gyp Domain Proteinsmentioning

confidence: 99%

“…A screen of potential phosphodiesterases for 3=3=-cyclic GMP-AMP from V. cholerae identified three HD-GYP domain proteins, VCA0210, VCA0681, and VCA0931, which were capable of hydrolysis of the cyclic dinucleotide into 5=-pApG, with VCA0681 having an additional 5=-nucleotidase activity to generate 5=-ApG (87). The nucleotidase and phosphodiesterase activities were associated with the HD and HD-GYP domains, respectively, which are present in tandem (87). All three proteins hydrolyze 3=3=-cyclic GMP-AMP specifically, with no activity against other cyclic GMP-AMP forms with different phosphodiester linkages, to include the mammalian innate immunity regulator 2=3=-cyclic GMP-AMP.…”

Section: Further Substrates For Hd-gyp Domain Proteinsmentioning

confidence: 99%

Progress in Understanding the Molecular Basis Underlying Functional Diversification of Cyclic Dinucleotide Turnover Proteins

2017

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Cyclic di-GMP was the first cyclic dinucleotide second messenger described, presaging the discovery of additional cyclic dinucleotide messengers in bacteria and eukaryotes. The GGDEF diguanylate cyclase (DGC) and EAL and HD-GYP phosphodiesterase (PDE) domains conduct the turnover of cyclic di-GMP. These three unrelated domains belong to superfamilies that exhibit significant variations in function, and they include both enzymatically active and inactive members, with a subset involved in synthesis and degradation of other cyclic dinucleotides. Here, we summarize current knowledge of sequence and structural variations that underpin the functional diversification of cyclic di-GMP turnover proteins. Moreover, we highlight that superfamily diversification is not restricted to cyclic di-GMP signaling domains, as particular DHH/DHHA1 domain and HD domain proteins have been shown to act as cyclic di-AMP phosphodiesterases. We conclude with a consideration of the current limitations that such diversity of action places on bioinformatic prediction of the roles of GGDEF, EAL, and HD-GYP domain proteins.KEYWORDS cyclic dinucleotide second messenger, GGDEF domain, EAL domain, HD-GYP domain, DHH/DHHA1 domain, cyclic GAMP, cyclic di-AMP, cyclic di-GMP, second messenger T he dinucleotide cyclic di-GMP is the most abundant second messenger in bacteria. It promotes the environmental lifestyle switch between sessility and motility, as well as the host-related lifestyle switch between acute and chronic/benign infection. A hallmark of the cyclic di-GMP signaling network is an apparent redundancy of cyclic di-GMP turnover proteins encoded in one genome. However, many of these proteins have distinct N-terminal sensing and signaling domains, suggesting that their activities in cyclic di-GMP turnover respond posttranslationally to various (and different) intraand extracellular signals. In gross terms, the number of cyclic di-GMP turnover proteins is linearly correlated with genome size within the different bacterial phyla, with Thermotogae having one of the highest cyclic di-GMP-related "IQs," the density of enzymes per megabase pair, with some species harboring over 100 cyclic di-GMP turnover proteins (http://www.ncbi.nlm.nih.gov/Complete_Genomes/c-di-GMP.html). As in other domain superfamilies, extensive sequence diversity exists. Here, we review the knowledge on the translation of sequence diversity of cyclic di-GMP turnover proteins into functional diversity. We conclude by discussing whether and how a unified nomenclature for cyclic di-GMP turnover proteins can be established.

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“…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). A new study by Gao et al [12] has now identified the first three 3′3′-cGAMP-specific PDEs in V. cholerae and provided detailed insights into their enzymatic mechanisms.…”

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confidence: 99%