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

Abstract

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.

Alterations of c‐di‐GMP turnover proteins modulate semi‐constitutive rdar biofilm formation in commensal and uropathogenic Escherichia coli

“…In addition, we identified three novel EAL domain proteins PdeU1, PdeU2, and PdeU3 in UPEC strains (Table ); PdeU1 was present in B‐11870 and 80//6, PdeU2 was found in B‐11870, and PdeU3 in B‐8638. Extended conserved aa signatures are critical for PDE activity (Liang, ; Römling, Liang, & Dow, ; Römling et al., ). Conservation of the signature motifs of catalytic residues indicated that only PdeU1 is potentially active (Figure S4).…”

“…Overall, strains showed variability in the number of c-di-GMP turnover proteins ( (Liang, 2015;Römling, Liang, & Dow, 2017;Römling et al, 2013). Conservation of the signature motifs of catalytic residues indicated that only PdeU1 is potentially active ( Figure S4).…”

Phosphodiesterase Genes Regulate Amylovoran Production, Biofilm Formation, and Virulence in Erwinia amylovora

“…Therefore, our data indicate that edcA is not a PDE in E. amylovora. PDEs respond to a wide range of specific stimuli and can be functional in localized areas within the cell (36,37). The experimental conditions under which we evaluated c-di-GMP levels might restrict the expression and/or enzymatic activity of PdeA and PdeB, thus not resulting in a measurable impact on c-di-GMP levels in the cell under these conditions, whereas these enzymes might have more significant contributions in other environments.…”

Second messengers and divergent HD‐GYP phosphodiesterases regulate 3′,3′‐cGAMP signaling

“…Diverse signaling pathways are comprised of specific enzyme classes that produce and degrade a signal, as well as biomolecules that respond to the signal. In cyclic dinucleotide signaling, synthases produce the cyclic dinucleotide (CDN) signal from nucleotide triphosphate (NTP) substrates, phosphodiesterases (PDEs) degrade the CDN via hydrolysis of one or both phosphodiester linkages, and effectors, including transcription factors, enzymes, and riboswitches, respond to the CDN signal (Römling et al , ; ). So far, three CDN second messengers have been found to control critical bacterial processes, including biofilm formation, cell wall homeostasis, intestinal colonization and transient surface interactions (Davies et al , ; Corrigan and Gründling, ; Römling et al , ; Hallberg et al , ).…”