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Review
. 2012 Jul;21(7):929-48.
doi: 10.1002/pro.2093. Epub 2012 Jun 5.

Sensing the messenger: the diverse ways that bacteria signal through c-di-GMP

Petya Violinova Krasteva  1 , Krista Michelle Giglio, Holger Sondermann
Affiliations
Review

Sensing the messenger: the diverse ways that bacteria signal through c-di-GMP

Petya Violinova Krasteva et al. Protein Sci. 2012 Jul.

Abstract

An intracellular second messenger unique to bacteria, c-di-GMP, has gained appreciation as a key player in adaptation and virulence strategies, such as biofilm formation, persistence, and cytotoxicity. Diguanylate cyclases containing GGDEF domains and phosphodiesterases containing either EAL or HD-GYP domains have been identified as the enzymes controlling intracellular c-di-GMP levels, yet little is known regarding signal transmission and the sensory targets for this signaling molecule. Although limited in number, identified c-di-GMP receptors in bacteria are characterized by prominent diversity and multilevel impact. In addition, c-di-GMP has been shown to have immunomodulatory effects in mammals and several eukaryotic c-di-GMP sensors have been proposed. The structural biology of c-di-GMP receptors is a rapidly developing field of research, which holds promise for the development of novel therapeutics against bacterial infections. In this review, we highlight recent advances in identifying bacterial and eukaryotic c-di-GMP signaling mechanisms and emphasize the need for mechanistic structure-function studies on confirmed signaling targets.

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Figures

Figure 1
Figure 1
Overview of c-di-GMP signaling. (A) Biofilm formation. High levels of c-di-GMP in bacterial cells are often associated with cell adhesion, matrix secretion, and biofilm formation. (B) C-di-GMP signaling. Opposing activities of diguanylate cyclases (DGCs) with GGDEF domains and phosphodiesterases (PDEs) with EAL or HD-GYP domains control cellular c-di-GMP levels. The domains are often linked to regulatory domains, which control overall enzyme activity and cellular localization. In addition, several cellular programs have been shown to be under c-di-GMP control.
Figure 2
Figure 2
Effectors or receptors for c-di-GMP. Modules and proteins for c-di-GMP binding are diverse. While several bacterial effectors have been studied extensively, only one well-validated target on host cells has been discovered. Others await further characterization.
Figure 3
Figure 3
Modes of c-di-GMP effector function. Based on structural studies several modes of c-di-GMP action on effector proteins have been described, including the release of autoinhibitory interactions (A), allosteric regulation (B), major structural rearrangements (C) and/or dimerization (D). In addition, c-di-GMP itself can adopt several distinct conformations when bound to proteins.
Figure 4
Figure 4
GGDEF domains and diguanylate cyclases. (A) Prototypical GGDEF domain structure. The PleD GGDEF domain bound to GTP-alpha-S is shown (PDB code: 2V0N). The GGDEF motif is colored yellow. The position of the I-site is highlighted as small spheres. The sequence logo highlights several conserved motifs extending in to the linker upstream of the GGDEF domain fold. (B) Product-inhibited structure of full-length PleD. The structure of a PleD dimer activated by BeF−3 bound to one REC domain is shown. The enzyme is inhibited by a stacked c-di-GMP dimer that occupies the I-site on the GGDEF domains (inset). (C) Models for the regulatory cycle for PleD and WspR. The models highlight conserved and unique feature that control enzymatic function of the two proteins.
Figure 5
Figure 5
Structure of a canonical EAL domain. (A) EAL domain fold. The EAL domain was extracted for the full-length crystal structure of the light-regulated phoshphodiesterase BlrP1 (PDB code: 3GFZ). Metal ion and c-di-GMP binding sites are shown. (B) EAL domain dimer. Several structures of EAL domains show a dimeric assembly that is likely relevant for c-di-GMP binding and establishing the catalytically competent state.
Figure 6
Figure 6
Structure of an HD-GYP domain fold. (A) Overall fold. The modular nature of a full-length HD-GYP domain-containing protein is shown (PDB code: 3TM8). (B) Close-up view of the putative nucleotide binding site.
Figure 7
Figure 7
Model for LapD-mediated signaling. The composite structural model highlights the proposed conformational changes of the transmembrane, c-di-GMP effector LapD. Switching in the intracellular domains regulates the conformation of its periplasmic output domain, which differentially interacts with a protease, LapG, that in turn controls the stability of a cell surface adhesin, and hence biofilm formation. Intracellular regulators as well as environmental signals are well-established for this system.,
Figure 8
Figure 8
Overview of REC domain dimerization. (A) Canonical REC domains.– (B) VpsT dimerization.
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