title: 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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Ute.Romling@ki.se ZXLiang@ntu.edu.sg.
authors.forename: Ute
authors.identifier: http://orcid.org/0000-0003-3812-6621
authors.initials: U
authors.lastname: Römling
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore Ute.Romling@ki.se ZXLiang@ntu.edu.sg.
authors.forename: Zhao-Xun
authors.identifier: http://orcid.org/0000-0002-3128-1330
authors.initials: ZX
authors.lastname: Liang
authors.affiliation: School of Microbiology, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: J Maxwell
authors.initials: JM
authors.lastname: Dow
mesh_terms: D001419:Bacteria / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D000071184:Pharmacogenomic Variants
chemical_list: D001426:Bacterial Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP
keywords: DHH/DHHA1 domain; EAL domain; GGDEF domain; HD-GYP domain; cyclic GAMP; cyclic di-AMP; cyclic di-GMP; cyclic dinucleotide second messenger; second messenger