Family G4
Summary for family G4
| Family type peptidase | G04.001 - Tiki1 peptidase (Homo sapiens), MEROPS Accession MER0105341 (peptidase unit: 20-505) |
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| History | The Wnt signalling pathway is important during embryogenesis. Tiki1 is a transmembrane protein expressed in the dorsal Spemann-Mangold Organizer, which is a cluster of cells in the developing embryo of an amphibian that induces development of the central nervous system. Tiki1 antagonizes Wnt signalling by releasing an octopeptide from the N-terminus of a Wnt protein, which does not affect secretion of the Wnt protein, but does prevent it from binding its receptor (Zhang et al., 2012). |
| Catalytic type | Glutamic |
| Active site residues | E161 |
| Active site | Inhibition by chelating agents indicated that Tiki1 might be a metallopeptidase (Zhang et al., 2012). From its albeit distant sequence similarity to TraB proteins and erythromycin esterase, Tiki1 had been assumed to be a cocatalytic zinc metallopeptidase, binding two ions of zinc per molecule. Zinc-binding residues have been predicted to be His60,Glu87, Arg304, Asn305, His332, and Glu161 to be a catalytic residue (Sanchez-Pulido & Ponting, 2013). If correct, this would be the first occurrence of an Asn being a metal ligand in a metallopeptidase, Tiki 1 was also shown to be structurally related to the RRSP domain from the MARTX toxin of the pathogenic bacterium Vibrio vulnificatus (G06.001, Sanchez-Pulido & Ponting, 2013) for which the structure has been solved (Biancucci et al., 2018). The metal ions in erythromycin esterase are thought to be non-catalytic, the RRSP peptidase does not contain zinc, and both enzymes have a His/Glu dyad thought to be responsible for activating water (Morar et al., 2012). It has been suggested that the zinc in Tiki 1 is also not catalytic but structural (Biancucci et al., 2018). |
| Activities and specificities | An N-terminal octapeptide is removed from the Wnt-3a protein, with cleavage occurring at at Leu+Ala bond (Zhang et al., 2012). |
| Inhibitors | Zhang et al., 2012 have shown that Wnt-3a processing by Tiki1 is inhibited by the metal chelating agent 1,10-phenanthroline but not by bestatin. |
| Molecular structure | Tiki is a secreted protein with an N-terminal signal peptide and a C-terminal transmembrane region (Zhang et al., 2012). From the proposed relationship to erythromycin esterases and MARTX toxin, Tiki1 (Sanchez-Pulido & Ponting, 2013) would represent a glutamic endopeptidase in clan GC. |
| Clan | GC |
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