VapC-like PIN domain of human telomerase-binding protein EST1, Smg6, and other similar eukaryotic homologs.
Nonsense-mediated decay (NMD) factors, Smg5 and Smg6 are essential to the post-transcriptional regulatory pathway, NMD, which recognizes and rapidly degrades mRNAs containing premature translation termination codons. In vivo, the Smg6 PIN (PilT N terminus) domain elicits degradation of bound mRNAs, as well as, metal ion dependent, degradation of single-stranded RNA, in vitro. The PIN domain belongs to a large nuclease superfamily. The structural properties of the PIN domain indicate its putative active center, consisting of invariant acidic amino acid residues (putative metal-binding residues), is geometrically similar in the active center of structure-specific 5' nucleases (also known as Flap endonuclease-1-like), PIN-domain ribonucleases of eukaryotic rRNA editing proteins, and bacterial toxins of toxin-antitoxin (TA) operons. PIN domains within this subgroup contain four highly conserved acidic residues (putative metal-binding, active site residues) which cluster at the C-terminal end of the beta-sheet and form a negatively charged pocket near the center of the molecule. Point mutation studies of the conserved aspartate residues in the catalytic center of the Smg6 PIN domain revealed that Smg6 is the endonuclease involved in human NMD. However, Smg5 lacks several of these key catalytic residues and does not degrade single-stranded RNA, in vivo. Eukaryotic Smg6 PIN domains are present at the C-terminal end of the telomerase activating proteins, EST1.
Comment:based 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 5 conserved catalytic residues are found.
Comment:Note that SMG5, a related PIN_VapC-like family member lacks all but a single aspartic acid residue in the active site and consequently is inactive as a nuclease
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