CARE and WYL domains: ligand-binding regulators of prokaryotic defense systems

CRISPR-Cas adaptive immunity systems of bacteria and archaea insert fragments of virus or plasmid DNA as spacer sequences into CRISPR repeat loci. Processed transcripts encompassing these spacers guide the cleavage of the cognate foreign DNA or RNA. Most CRISPR-Cas loci, in addition to recognized cas genes, also include genes that are not directly implicated in spacer acquisition, CRISPR transcript processing or interference. Here we comprehensively analyze sequences, structures and genomic neighborhoods of one of the most widespread groups of such genes that encode proteins containing a predicted nucleotide-binding domain with a Rossmann-like fold, which we denote CARE (CRISPR-associated Rossmann fold). Several CARE protein structures have been determined but functional characterization of these proteins is lacking. The CARE domain is most frequently combined with a C-terminal winged helix-turn-helix DNA-binding domain and effector domains most of which are predicted to possess DNase or RNase activity. Divergent CARE domains are also found in RtcR proteins, sigma-54 dependent regulators of the rtc RNA repair operon. CARE genes frequently co-occur with those coding for proteins containing the WYL domain with the Sm-like 5H3 13-barrel fold, which is also predicted to bind ligands. CRISPR-Cas and possibly other defense systems are predicted to be transcriptionally regulated by multiple ligand-binding proteins containing WYL and CARE domains which sense modified nucleotides and nucleotide derivatives generated during virus infection. We hypothesize that CARE domains also transmit the signal from the bound ligand to the fused effector domains which attack either alien or self nucleic acids, resulting, respectively, in immunity complementing the CRISPR-Cas action or in dormancy/programmed cell death.