VapC-like PIN domain of ribonucleases (toxins), VapC and FitB, of prokaryotic toxin/antitoxin operons, Pyrococcus horikoshii protein PH0500, and other similar bacterial and archaeal homologs.
PIN (PilT N terminus) domain-containing proteins of prokaryotic toxin/antitoxin (TA) operons, such as, Mycobacterium tuberculosis VapC of the VapBC (virulence associated proteins) TA operon, and Neisseria gonorrhoeae FitB of the FitAB (fast intracellular trafficking) TA operon, as well as, the archaeal Pyrococcus horikoshii protein PH0500 are included in this family. Toxins of TA operons are believed to be involved in growth inhibition by regulating translation and are nearly always co-expressed with an antitoxin, a cognate protein inhibitor, forming an inert protein complex. Disassociation of the complex activates the ribonuclease activity of the toxin. In N. gonorrhoeae, FitA and FitB form a heterodimer: FitA is the DNA binding subunit and FitB contains a ribonuclease activity that is blocked by the presence of FitA. A tetramer of FitAB heterodimers binds DNA from the fitAB upstream promoter region with high affinity. This results in both sequestration of FitAB and repression of fitAB transcription. It is thought that FitAB release from the DNA and subsequent dissociation both slows N. gonorrhoeae replication and transcytosis by an as yet undefined mechanism. The toxin M. tuberculosis VapC is a structural homolog of N. gonorrhoeae FitB, but their antitoxin partners, VapB and FitA, respectively, differ structurally. The M. tuberculosis VapC-5 is proposed to be both an endoribonuclease and an exoribonuclease that can act on free RNA in a similar manner to the endo and exonuclease Flap endonuclease-1 (FEN1). VapC-like toxins are structural homologs of FEN1-like PIN domains, but lack the extensive arch/clamp region and the H3TH (helix-3-turn-helix) domain, an atypical helix-hairpin-helix-2-like region, seen in FEN1-like PIN domains. PIN domains within this group typically contain three or four conserved acidic residues that cluster at the C-terminal end of the beta-sheet and form a negatively charged pocket near the center of the molecule. These putative active site residues are thought to bind Mg2+ and/or Mn2+ ions and be essential for single-stranded ribonuclease activity. VapC-like PIN domains are single domain proteins that form dimers and dimerization configures the active sites in a groove along the long-axis of the structure.
Comment: based on Mycobacterium tuberculosis VapC-15 structure, and on structure and experimental evidence from PIN-superfamily members belonging to the FEN-like, VapC-like, PRORP-like, and LabA-like families
Comment:The PIN domain superfamily contains three highly conserved catalytic residues which coordinate metal ions; in some members, additional metal coordinating residues can be found while some others lack several of these key catalytic residues. In this subgroup 3-5 conserved catalytic residues are found.
Structure:4CHG; Mycobacterium tuberculosis VapBC-15 binds Mg2+ and Mn2+
Jiyao W et al.(2023). "The conserved domain database in 2023.",