Cyclic di-AMP, a second messenger of primary importance: tertiary structures and binding mechanisms
Open Access
- 25 February 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 48 (6), 2807-2829
- https://doi.org/10.1093/nar/gkaa112
Abstract
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. 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. 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. 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 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 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.Funding Information
- National Library of Medicine
- National Natural Science Foundation of China (31770087, 31970074, 31270105)
- Fundamental Research Funds for the Central Universities (2662017PY112, 2662015PY175)
- China Postdoctoral Science Foundation (2018M630872)
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