![]() ( C, D) Extended conformations of c-di-GMP from its complex with the EAL domain of Klebsiella pneumoniae photoreceptor BlrP1, PDB: 3GFX (C), and c-di-AMP from its complex with the RECON protein, PDB: 5UXF (D) the two bases are wide apart. aureus) (B) the two bases are oriented in an almost parallel fashion. cholerae protein PlzD) (A), and c-di-AMP from the PDB entry 4YP1 (in complex with the cation-proton antiporter CpaA from S. ( A, B) U-type conformations of c-di-GMP from the PDB entry 2RDE (in complex with the V. Structures of c-di-GMP and c-di-AMP molecules. The c-di-GMP conformations and binding mechanisms have been analyzed in detail ( 8) and those of c-di-AMP are discussed below. However, while c-di-GMP is typically found in a dimer form with four guanine bases forming a parallel stack (Figure (Figure1E), 1E), c-di-AMP is almost always seen in a monomer form with its adenine bases either parallel (Figure (Figure1B) 1B) or arranged at an angle with each other (Figure (Figure1F). Both molecules can be seen in a wide range of conformations, from two nucleobases located side-by-side (Figure (Figure1A, B) 1A, B) to fully stretched conformations where the bases are far apart (Figure (Figure1C, D). Like its better-studied sibling c-di-GMP, c-di-AMP consists of two nucleotide moieties bound by 3′→5′ phosphodiester bridges that form a 12-atom central ribose-phosphate ring. Although it is generally not a good idea to name a protein domain after a specific enzymatic activity (which may be lacking or altered), we are using the same name here, as all DisA_N domains characterized so far exhibited the DAC activity. The DisA_N domain is often referred to as the DAC domain ( 3, 7). The N-terminal domain of DisA, DisA_N, has been identified as a diadenylate cyclase (DAC), responsible for producing c-di-AMP from two molecules of ATP this activity is suppressed when DisA encounters branched DNA structures of stalled replication forks ( 3, 4). The discovery of c-di-AMP in a biological system happened much later, in 2008, when it was serendipitously found in the crystal structure of the DNA integrity scanning protein DisA from Thermotoga maritima, whose close homolog in Bacillus subtilis is a sporulation checkpoint protein that senses DNA double-strand breaks ( 3, 4). It was initially synthesized in 1985 as a potential inhibitor of RNA polymerase ( 1) five years later, it was tested for its (in)ability to replace the closely related cyclic diguanylate (c-di-GMP) as an activator of the bacterial cellulose synthase ( 2). ![]() We also compare the mechanisms of c-di-AMP and c-di-GMP binding by the respective receptors that allow these two cyclic dinucleotides to control very different biological functions.Ĭyclic bis(3′→5′) dimeric adenosine monophosphate (cyclic di-AMP or c-di-AMP) is a dinucleotide second messenger that is widespread in bacteria and archaea. We describe seven kinds of non-covalent–π interactions between c-di-AMP and its receptor proteins, including π–π, C–H–π, cation–π, polar–π, hydrophobic–π, anion–π and the lone pair–π interactions. We discuss how these c-di-AMP molecules are bound to the protein and riboswitch receptors and what kinds of interactions account for the specific high-affinity binding of the c-di-AMP ligand. ![]() We review here the tertiary structures of the domains that regulate c-di-AMP synthesis and signaling, and the mechanisms of c-di-AMP binding, including the principal conformations of c-di-AMP, observed in various crystal structures. The primary importance of c-di AMP stems from its essentiality for many bacteria under standard growth conditions and the ability of several eukaryotic proteins to sense its presence in the cell cytoplasm and trigger an immune response by the host cells. Cyclic diadenylate (c-di-AMP) is a widespread second messenger in bacteria and archaea that is involved in the maintenance of osmotic pressure, response to DNA damage, and control of central metabolism, biofilm formation, acid stress resistance, and other functions.
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