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• W2078971151 abstract "Characterization of an activated diguanylate cyclase reported in this issue of Structure by Wassmann et al., 2007Wassmann P. Chan C. Paul R. Beck A. Heerklotz H. Jenal U. Schirmer T. Structure. 2007; 15 (this issue): 915-927Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar reveals how phosphorylation promotes dimerization necessary for synthesis of the second messenger c-di-GMP, establishes the catalytic mechanism, and identifies a widely conserved mode of product inhibition. Characterization of an activated diguanylate cyclase reported in this issue of Structure by Wassmann et al., 2007Wassmann P. Chan C. Paul R. Beck A. Heerklotz H. Jenal U. Schirmer T. Structure. 2007; 15 (this issue): 915-927Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar reveals how phosphorylation promotes dimerization necessary for synthesis of the second messenger c-di-GMP, establishes the catalytic mechanism, and identifies a widely conserved mode of product inhibition. Cyclic nucleotides are widely used as second messengers for signal transduction in both prokaryotes and eukaryotes. The cyclic dinucleotide bis-(3′–5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) has emerged as an important second messenger widely and exclusively used by eubacteria (Jenal and Malone, 2006Jenal U. Malone J. Annu. Rev. Genet. 2006; 40: 385-407Crossref PubMed Scopus (503) Google Scholar, Romling et al., 2005Romling U. Gomelsky M. Galperin M.Y. Mol. Microbiol. 2005; 57: 629-639Crossref PubMed Scopus (550) Google Scholar). In systems characterized to date, c-di-GMP signaling appears to play a specialized role, regulating transitions between motile and sessile lifestyles by coordinating the many cellular functions necessary for existence as isolated planktonic cells or within multicellular communities of biofilms. The environmental cues that regulate c-di-GMP pathways are mostly unknown, and the downstream targets of c-di-GMP that elicit the cellular responses are just beginning to be discovered. In contrast to the limited understanding of signal input and output, significant progress has been made in characterizing the conserved synthetic and degradative enzymes that control intracellular concentrations of c-di-GMP. Synthesis of c-di-GMP from two molecules of GTP is catalyzed by diguanylate cyclases (DGCs) containing GGDEF domains, named after the conserved sequence motif that constitutes part of the active site (Figure 1). Degradation of c-di-GMP to GMP is catalyzed by phosphodiesterases (PDEs) containing either EAL or HD-GYP domains, also named after conserved sequence motifs. Several thousand GGDEF, EAL, and HD-GYP domains have been identified in a few hundred sequenced bacterial genomes. The genome of Escherichia coli encodes 3 dozen GGDEF and EAL domain proteins while various Vibrio genomes each encode ∼100 such proteins. The domains are modular and typically are found coupled to a variety of other signaling domains within multidomain proteins. GGDEF and EAL domains (either inactive or active and presumably antagonistic) are often found together within a single protein. Not surprisingly, given its role as a second messenger, intracellular levels of c-di-GMP appear to be exquisitely regulated, and indeed, unregulated production of c-di-GMP is toxic to cells (Christen et al., 2006Christen B. Christen M. Paul R. Schmid F. Folcher M. Jenoe P. Meuwly M. Jenal U. J. Biol. Chem. 2006; 281: 32015-32024Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, Ryjenkov et al., 2005Ryjenkov D.A. Tarutina M. Moskvin O.V. Gomelsky M. J. Bacteriol. 2005; 187: 1792-1798Crossref PubMed Scopus (462) Google Scholar). In this issue of Structure, Schirmer and colleagues report the crystal structure of activated PleD (Wassmann et al., 2007Wassmann P. Chan C. Paul R. Beck A. Heerklotz H. Jenal U. Schirmer T. Structure. 2007; 15 (this issue): 915-927Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), a diguanylate cyclase involved in pole remodeling during the generation of surface-adherent stalked cells and motile swarmer cells in the developmental cycle of Caulobacter crescentus (Hecht and Newton, 1995Hecht G.B. Newton A. J. Bacteriol. 1995; 177: 6223-6229Crossref PubMed Google Scholar). PleD is the response regulator component of a His-Asp phosphotransfer (two-component) pathway and consists of three domains: two ∼140-residue receiver domains and an ∼160-residue C-terminal GGDEF DGC effector domain. Phosphorylation of the first receiver domain results in ∼35-fold stimulation of cyclase activity (Wassmann et al., 2007Wassmann P. Chan C. Paul R. Beck A. Heerklotz H. Jenal U. Schirmer T. Structure. 2007; 15 (this issue): 915-927Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). In the reported structure, phosphorylation is mimicked by the presence of BeF3−, a noncovalent stable analog of the phosphoryl moiety of the physiological phospho-aspartate (Wemmer and Kern, 2005Wemmer D.E. Kern D. J. Bacteriol. 2005; 187: 8229-8230Crossref PubMed Scopus (33) Google Scholar). However, the presence of c-di-GMP locks the catalytic domains in a nonproductive orientation, revealing a new mode of product inhibition that is redundant with the previously documented negative feedback mechanism (Chan et al., 2004Chan C. Paul R. Samoray D. Amiot N.C. Giese B. Jenal U. Schirmer T. Proc. Natl. Acad. Sci. USA. 2004; 101: 17084-17089Crossref PubMed Scopus (362) Google Scholar, Christen et al., 2006Christen B. Christen M. Paul R. Schmid F. Folcher M. Jenoe P. Meuwly M. Jenal U. J. Biol. Chem. 2006; 281: 32015-32024Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). Additionally, a GTPαS substrate analog bound at the active site provides direct evidence for the previously postulated two-metal assisted mechanism for phosphodiester formation that occurs in structurally related adenylate cyclases and polymerases (Chan et al., 2004Chan C. Paul R. Samoray D. Amiot N.C. Giese B. Jenal U. Schirmer T. Proc. Natl. Acad. Sci. USA. 2004; 101: 17084-17089Crossref PubMed Scopus (362) Google Scholar, Sinha and Sprang, 2006Sinha S.C. Sprang S.R. Rev. Physiol. Biochem. Pharmacol. 2006; 157: 105-140Crossref PubMed Scopus (70) Google Scholar). The structures of activated (Wassmann et al., 2007Wassmann P. Chan C. Paul R. Beck A. Heerklotz H. Jenal U. Schirmer T. Structure. 2007; 15 (this issue): 915-927Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar) and nonactivated (Chan et al., 2004Chan C. Paul R. Samoray D. Amiot N.C. Giese B. Jenal U. Schirmer T. Proc. Natl. Acad. Sci. USA. 2004; 101: 17084-17089Crossref PubMed Scopus (362) Google Scholar) PleD, together, allow postulation of the full repertoire of monomeric, dimeric, catalytically competent, and multiple product-inhibited states relevant to PleD regulation (see Figure 7 in Wassmann et al., 2007Wassmann P. Chan C. Paul R. Beck A. Heerklotz H. Jenal U. Schirmer T. Structure. 2007; 15 (this issue): 915-927Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Acitvation of PleD requires dimerization and this appears to be the sole regulatory function of the first receiver domain. Phosphorylation alters the molecular surface of the receiver domain, promoting tight homo-dimerization through the α4-β5-α5 faces, with an affinity ∼10-fold greater than that of the unphosphorylated domains, which were observed to associate as a loosely packed dimer. Dimerization of the receiver domains facilitates productive interaction of the DGC catalytic domains, bringing together two GTP molecules within the active sites for cyclization. Notably, the receiver domains do not appear to allosterically influence catalysis. Interestingly, this activation mechanism parallels that observed in the large family of OmpR/PhoB response regulator transcription factors (Gao et al., 2007Gao R. Mack T.R. Stock A.M. Trends Biochem. Sci. 2007; 32: 225-234Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). Specifically, phosphorylation results in a similar increase in dimerization affinity; dimerization occurs through the same α4-β5-α5 interface and involves residues conserved in both the OmpR/PhoB family and PleD; and activation results from intermolecular contacts rather than intrachain communication between receiver and effector domains. Thus in these proteins, the versatile receiver domain employs a common mechanism to activate structurally and functionally disparate effector domains. This mode of activation of PleD is especially satisfying in that it need not be restricted to the ∼10% of diguanylate cyclases that contain receiver domains. A similar strategy for DGC domain activation could presumably be coupled to many different types of signaling domains, each with its own mechanism for regulating dimerization. High catalytic activity coupled to product inhibition is an optimal mechanism for generating temporally and or spatially localized spikes of second messenger. Such localization is likely important to restrict signaling output to defined targets within cells that contain many c-di-GMP pathways. PleD exhibits two apparently redundant noncompetitive modes of binding c-di-GMP, both of which immobilize the catalytic domains in nonproductive orientations. One mode of product binding crosslinks the second receiver domain with the catalytic domain (Chan et al., 2004Chan C. Paul R. Samoray D. Amiot N.C. Giese B. Jenal U. Schirmer T. Proc. Natl. Acad. Sci. USA. 2004; 101: 17084-17089Crossref PubMed Scopus (362) Google Scholar). The other mode, revealed in the current structure, crosslinks two catalytic domains. The latter mode is potentially available to any DGC, and the presence of the RXXD inhibition site sequence motif in ∼60% of all GGDEF domains suggests that product inhibition is a general feature of diguanylate cyclases. Although the domain architecture of PleD is representative of only a small fraction of diguanylate cyclases, characterization of BeF3−-activated PleD provides insight to features that are probably fundamental to many c-di-GMP pathways. This study establishes the importance of dimerization for DGC activation and documents the lack of allosteric interactions between regulatory and catalytic domains, revealing a strategy amenable to many different types of dimerization domains. The identification of sites for c-di-GMP crosslinking of catalytic domains defines a general mechanism for product inhibition. Furthermore, it illustrates the important bidentate nature of the second messenger dinucleotide and its ability to crosslink different domains. This activity is likely to be predictive of its downstream role in signaling, facilitating associations of a variety of target proteins and or nucleic acids. Structure of BeF3−-Modified Response Regulator PleD: Implications for Diguanylate Cyclase Activation, Catalysis, and Feedback InhibitionWassmann et al.StructureAugust 14, 2007In BriefCyclic di-guanosine monophosphate (c-di-GMP) is a ubiquitous bacterial second messenger involved in the regulation of cell surface-associated traits and persistence. We have determined the crystal structure of PleD from Caulobacter crescentus, a response regulator with a diguanylate cyclase (DGC) domain, in its activated form. The BeF3− modification of its receiver domain causes rearrangement with respect to an adaptor domain, which, in turn, promotes dimer formation, allowing for the efficient encounter of two symmetric catalytic domains. Full-Text PDF Open Archive" @default.
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• W2078971151 title "Diguanylate Cyclase Activation: It Takes Two" @default.
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