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Classic Spotlight: Cyclic Di-GMP, the Molecule That Makes the Bacterial World Stop Going =Round George A. O’Toole Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA

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riginally discovered in 1986 by Ross and colleagues as a regulator of cellulose synthesis (1, 2), cyclic diguanylate (c-diGMP) has emerged as a global regulator of bacterial biology. This cyclic dinucleotide has a key role in the motile-to-sessile transition by controlling flagellar and pilus-mediated motility, exopolysaccharide production, and adhesion localization and has been implicated in pathogenic and symbiotic interactions. Several papers in the Journal of Bacteriology (JB) made key contributions to understanding how c-di-GMP impacts bacterial biology by characterizing the enzymes that make and break this molecule. A 1998 report by Tal and colleagues described the isolation of enzymes with diguanylate cyclase (DGC) activity, required to synthesize c-di-GMP, and phosphodiesterase (PDE) activity, which degrades this cyclic dinucleotide (3). Using the N-terminal sequences of these proteins, this group was able to identify the genes coding for these enzymes in Acetobacter (now Komagataeibacter) xylinum and thus their predicted protein sequences and the domains associated with these activities (3). Disruption of these genes altered c-di-GMP-regulated activities and levels of this cyclic dinucleotide in this microbe. The DGCs identified by this group had a conserved GGDEF amino acid motif. In another paper in JB published a few years earlier, Hecht and Newton had discovered PleD, a regulatory protein in Caulobacter, with a conserved GGDEF motif (4). Despite the fact that the GGDEF domain was not linked to c-di-GMP metabolism in this publication, Tal et al. (3) adopted this nomenclature; this moniker is still used as shorthand to describe the domain associated with DGC activity. Tal et al. (3) referred to the motif associated with the PDE enzymes as the “EAL domain,” also still common parlance in the field. Thus, this group was able to link the known DGC and PDE activities with protein sequences, and they realized that the domains linked to these activities were broadly conserved in bacteria (3). Several years later, in 2005, a report in JB by Schmidt, Ryjenkov, and Gomelsky demonstrated the specificity of DGC activity and its conservation across a number of bacterial groups (5). They showed that DGCs are required for the synthesis of c-di-GMP from two molecules of GTP (but not ATP) and that DGC activity is associated with the conserved “GGDEF” domain. This work also noted an important potential role for various “input” domains regulating DGC activity. In the same year, Ryjenkov et al. also reported the first in vitro evidence that proteins with the

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EAL domains could specifically catalyze the degradation of cdi-GMP (but not cyclic AMP) to its linear form (5=pGpG) (6). Ryjenkov and colleagues also proposed the existence of inactive EAL domains, which was confirmed in subsequent years. Both reports highlighted the nearly ubiquitous nature of these domains. Together, these works published in JB helped set the stage for the explosion of studies over the past decade around this key signaling molecule and ushered in the “Golden Age” of c-di-GMP. REFERENCES 1. Ross P, Aloni Y, Weinhouse H, Michaeli D, Weinberger-Ohana P, Mayer R, Benziman M. 1986. Control of cellulose synthesis in Acetobacter xylinum. A unique guanyl oligonucleotide is the immediate activator of the cellulose synthase. Carbohydr Res 149:101–117. 2. Ross P, Weinhouse H, Aloni Y, Michaeli D, Weinberger-Ohana P, Mayer R, Braun S, de Vroom E, van der Marel GA, van boom JH, Benziman M. 1987. Regulation of cellulose synthesis in Acetobacter xylinum by cyclic diguanylic acid. Nature 325:279 –281. 3. Tal R, Wong HC, Calhoon R, Gelfand D, Fear AL, Volman G, Mayer R, Ross P, Amikam D, Weinhouse H, Cohen A, Sapir S, Ohana P, Benziman M. 1998. Three cdg operons control cellular turnover of cyclic di-GMP in Acetobacter xylinum: genetic organization and occurrence of conserved domains in isoenzymes. J Bacteriol 180:4416 – 4425. 4. Hecht GB, Newton A. 1995. Identification of a novel response regulator required for the swarmer-to-stalked-cell transition in Caulobacter cresentus. J Bacteriol 177:6223– 6229. 5. Schmidt AJ, Ryjenkov DA, Gomelsky M. 2005. The ubiquitous protein domain EAL is a cyclic diguanylate-specific phosphodiesterase: enzymatically active and inactive EAL domains. J Bacteriol l 187:4774 – 4781. http: //dx.doi.org/10.1128/JB.187.14.4774-4781.2005. 6. Ryjenkov DA, Tarutina M, Moskvin OV, Gomelsky M. 2005. Cyclic diguanylate is a ubiquitous signaling molecule in bacteria: insights into biochemistry of the GGDEF protein domain. J Bacteriol 187:1792–1798. http://dx.doi.org/10.1128/JB.187.5.1792-1798.2005.

Citation O’Toole GA. 2016. Classic spotlight: cyclic di-GMP, the molecule that makes the bacterial world stop going =round. J Bacteriol 198:1553. doi:10.1128/JB.00190-16. Address correspondence to [email protected]. Copyright © 2016, American Society for Microbiology. All Rights Reserved. The views expressed in this Editorial do not necessarily reflect the views of the journal or of ASM.

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Classic Spotlight: Cyclic Di-GMP, the Molecule That Makes the Bacterial World Stop Going 'Round.

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