# The World of Cyclic Dinucleotides in Bacterial Behavior
### SMODS Domain Structure and Catalysis
Each domain is colored with different colors and the PDBID_chain and the Pfam name are shown for each branch. (**D**) The conserved fold found in most of these structures, all NTS members, is shown in brown overlaid on the DncV topology. (**E**) structural superposition of DncV (PDBID: 4U03) with other NTS members found in the panel (**C**) dendrogram, using the same colors to represent each domain. At the top of each structural alignment is shown the protein's name. NF90 is colored in purple (PDBID: 4 AT7), PAP is colored in orange (PDBID: 1Q78), cGAS is colored in dark green (PDBID: 5 XZE), Utp22 is colored in light green (PDBID: 4M5D), hOAS3.DI is colored in blue (PDBID: 453N), TRF4 is colored in light blue (PDBID: 3 NYB), EF_0920 is colored black (PDBID: 2 NRK), and Pol \(\mu\) is colored in green (PDBID: 2 IHM). More specifically, as revealed by Dali searches [79], the DncV structure shares structural similarities with eight members of the Nucleotidyltransferase superfamily (NTS): (**i**) proteins containing DZF domain (domain associated with Zinc Fingers, and PFAM model PF07528) such as nuclear factor NF90 and NF45; (**ii**) the catalytic domain of Poly(A) polymerase, PAP, (PAP_central domain, PF04928) [96]; (**iii**) the catalytic domain of eukaryotic cGAS enzymes (Mab-21 domain, PF03281); (**iv**) the D1 and D2 domains of the U3 small nucleolar RNA-associated protein 22 (Utp22) [97], in which the D1 domain matches the PFAM model named nucleolar RNA-associated proteins domain (Nrap, PF03813) and the D2 domain matches the Nrap protein PAP/OAS-like model (Nrap_D2, PF17403) [98]; (**v**) the OAS1-like domain of the dsRNA-activated oligoadenylate synthase (OAS) protein, which is described in the PFAM database as two domains: an N-terminal domain matching the NTP_transf_2 model (PF01909), also known as N-lobe of human OAS3 pseudoenzymatic domain DI (hOAS3.DI), and a C-terminal OAS1_C domain (PF10421), also known as C-lobe of hOAS3.DI [99]; (**vi**) the catalytic and central domains of Poly(A) RNA polymerase protein 2 (TRF4 gene), where the catalytic domain matches the NTP_transf_2 (PF01909) and the central domain matches the PAP_assoc model (Cid1 family poly A polymerase, PF03828) [100; 101]; (**vii**) proteins matching the GrpB domain (PF04229) [102], this domain is found in uncharacterized proteins such as EF_0920 from _Enterococcus faecalis_; and (**viii**) the palm subdomain (DNA_pol_B_palm, PF14792) [103] of the DNA polymerase \(\mu\) (Pol \(\mu\)) from the family X [104] that includes DNA polymerase \(\beta\), \(\gamma\), and \(\mu\)[105] (Figure 4E). All of these proteins share not only the NTase fold core, but also some secondary structures from the AGS-C domain (Figure 4D) suggesting that the domain interface is conserved in these families. It is worth mentioning that the AGS-C domain shares structural similarities with domains that are commonly associated with the catalytic domain of members of NTase, such as DZF C-terminal domain, OAS1_C, PAP_assoc, and Nrap_D2 (Figure 4E). DZF domains form dimers and heterodimers and are found in proteins involved in gene expression and RNA metabolism such as NF90 that forms a complex with NF45 and regulates genes expression [106]. Poly(A) polymerase (PAP) is involved in eukaryotic mRNA processing by its polyadenlation at the end of transcription process, so PAP incorporates ATP at the 3' end of Mrna [107]. In metazoans, the cGAS enzyme, which has a Mab_21 domain, binds cytoplasmic double-stranded DNA (dsDNA) to activate synthesis of 2'-3' cGAMP molecules and initiate host innate immune responses. Endogenous or exogenous dsDNA in the cytoplasm, which could be from damaged mitochondria or from an invasion of pathogenic bacteria or viruses, indicates major danger to eukaryotic cells. The cytosolic accumulation of 2'-3' cGAMP activates type-1 mediated stress-responses via STING and regulates autoimmunity in human cells [108].