title: C-di-GMP Synthesis: Structural Aspects of Evolution, Catalysis and Regulation.
abstract: Cellular levels of the second messenger cyclic di-guanosine monophosphate (c-di-GMP) are determined by the antagonistic activities of diguanylate cyclases and specific phosphodiesterases. In a given bacterial organism, there are often multiple variants of the two enzymes, which are tightly regulated by a variety of external and internal cues due to the presence of specialized sensory or regulatory domains. Dependent on the second messenger level, specific c-di-GMP receptors then control fundamental cellular processes, such as bacterial life style, biofilm formation, and cell cycle control. Here, I review the large body of data on structure-function relationships in diguanylate cyclases. Although the catalytic GGDEF domain is related to the respective domain of adenylate cyclases, the catalyzed intermolecular condensation reaction of two GTP molecules requires the formation of a competent GGDEF dimer with the two substrate molecules juxtaposed. This prerequisite appears to constitute the basis for GGDEF regulation with signal-induced changes within the homotypic dimer of the input domain (PAS, GAF, HAMP, etc.), which are structurally coupled with the arrangement of the GGDEF domains via a rigid coiled-coil linker. Alternatively, phosphorylation of a Rec input domain can drive GGDEF dimerization. Both mechanisms allow modular combination of input and output function that appears advantageous for evolution and rationalizes the striking similarities in domain architecture found in diguanylate cyclases and histidine kinases.
authors: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland. Electronic address: tilman.schirmer@unibas.ch.
authors: Tilman
authors: T
authors: Schirmer
mesh_terms: D001419:Bacteria / Q000201:enzymology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000096:biosynthesis; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008958:Models, Molecular; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D019761:Phosphorus-Oxygen Lyases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D029968:Escherichia coli Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D006160:Guanosine Triphosphate; D010727:Phosphoric Diester Hydrolases; D019761:Phosphorus-Oxygen Lyases; C060720:diguanylate cyclase; D006152:Cyclic GMP
keywords: diguanylate cyclase; regulation; second messenger; signal transduction; signaling