title: Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling.
abstract: Cyclic di- and linear oligo-nucleotide signals activate defenses against invasive nucleic acids in animal immunity; however, their evolutionary antecedents are poorly understood. Using comparative genomics, sequence and structure analysis, we uncovered a vast network of systems defined by conserved prokaryotic gene-neighborhoods, which encode enzymes generating such nucleotides or alternatively processing them to yield potential signaling molecules. The nucleotide-generating enzymes include several clades of the DNA-polymerase β-like superfamily (including Vibrio cholerae DncV), a minimal version of the CRISPR polymerase and DisA-like cyclic-di-AMP synthetases. Nucleotide-binding/processing domains include TIR domains and members of a superfamily prototyped by Smf/DprA proteins and base (cytokinin)-releasing LOG enzymes. They are combined in conserved gene-neighborhoods with genes for a plethora of protein superfamilies, which we predict to function as nucleotide-sensors and effectors targeting nucleic acids, proteins or membranes (pore-forming agents). These systems are sometimes combined with other biological conflict-systems such as restriction-modification and CRISPR/Cas. Interestingly, several are coupled in mutually exclusive neighborhoods with either a prokaryotic ubiquitin-system or a HORMA domain-PCH2-like AAA+ ATPase dyad. The latter are potential precursors of equivalent proteins in eukaryotic chromosome dynamics. Further, components from these nucleotide-centric systems have been utilized in several other systems including a novel diversity-generating system with a reverse transcriptase. We also found the Smf/DprA/LOG domain from these systems to be recruited as a predicted nucleotide-binding domain in eukaryotic TRPM channels. These findings point to evolutionary and mechanistic links, which bring together CRISPR/Cas, animal interferon-induced immunity, and several other systems that combine nucleic-acid-sensing and nucleotide-dependent signaling.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: A Maxwell
authors.initials: AM
authors.lastname: Burroughs
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Montgomery Blair High School, Magnet Program, Silver Spring, MD 20901, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Schäffer
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Lakshminarayan M
authors.initials: LM
authors.lastname: Iyer
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA aravind@ncbi.nlm.nih.gov.
authors.forename: L
authors.initials: L
authors.lastname: Aravind
mesh_terms: D001105:Archaea / Q000201:enzymology; D019843:Archaeal Proteins / Q000737:chemistry / Q000378:metabolism; D001419:Bacteria / Q000201:enzymology / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D005075:Biological Evolution; D064113:CRISPR-Cas Systems; D015280:DNA Restriction-Modification Enzymes / Q000378:metabolism; D056890:Eukaryota / Q000201:enzymology / Q000378:metabolism; D053263:Gene Regulatory Networks; D023281:Genomics; D017136:Ion Transport; D026901:Membrane Transport Proteins / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D019843:Archaeal Proteins; D001426:Bacterial Proteins; D015280:DNA Restriction-Modification Enzymes; D026901:Membrane Transport Proteins; D009711:Nucleotides; D014452:Ubiquitins; D009713:Nucleotidyltransferases