{PDOC00126} {PS00139; THIOL_PROTEASE_CYS} {PS00639; THIOL_PROTEASE_HIS} {PS00640; THIOL_PROTEASE_ASN} {BEGIN} ****************************************************** * Eukaryotic thiol (cysteine) proteases active sites * ****************************************************** Eukaryotic thiol proteases (EC 3.4.22.-) [1] are a family of proteolytic enzymes which contain an active site cysteine. Catalysis proceeds through a thioester intermediate and is facilitated by a nearby histidine side chain; an asparagine completes the essential catalytic triad. The proteases which are currently known to belong to this family are listed below (references are only provided for recently determined sequences). - Vertebrate lysosomal cathepsins B (EC 3.4.22.1), H (EC 3.4.22.16), L (EC 3.4.22.15), and S (EC 3.4.22.27) [2]. - Vertebrate lysosomal dipeptidyl peptidase I (EC 3.4.14.1) (also known as cathepsin C) [2]. - Vertebrate calpains (EC 3.4.22.52) (EC 3.4.22.53). Calpains are intracellular calcium-activated thiol protease that contain both a N-terminal catalytic domain and a C-terminal calcium-binding domain. - Mammalian cathepsin K, which seems involved in osteoclastic bone resorption [3]. - Human cathepsin O [4]. - Bleomycin hydrolase. An enzyme that catalyzes the inactivation of the antitumor drug BLM (a glycopeptide). - Plant enzymes: barley aleurain (EC 3.4.22.16), EP-B1/B4; kidney bean EP-C1, rice bean SH-EP; kiwi fruit actinidin (EC 3.4.22.14); papaya latex papain (EC 3.4.22.2), chymopapain (EC 3.4.22.6), caricain (EC 3.4.22.30), and proteinase IV (EC 3.4.22.25); pea turgor-responsive protein 15A; pineapple stem bromelain (EC 3.4.22.32); rape COT44; rice oryzain alpha, beta, and gamma; tomato low-temperature induced, Arabidopsis thaliana A494, RD19A and RD21A. - House-dust mites allergens DerP1 and EurM1. - Cathepsin B-like proteinases from the worms Caenorhabditis elegans (genes gcp-1, cpr-3, cpr-4, cpr-5 and cpr-6), Schistosoma mansoni (antigen SM31) and Japonica (antigen SJ31), Haemonchus contortus (genes AC-1 and AC-2), and Ostertagia ostertagi (CP-1 and CP-3). - Slime mold cysteine proteinases CP1 and CP2. - Cruzipain from Trypanosoma cruzi and brucei. - Throphozoite cysteine proteinase (TCP) from various Plasmodium species. - Proteases from Leishmania mexicana, Theileria annulata and Theileria parva. - Baculoviruses cathepsin-like enzyme (v-cath). - Drosophila small optic lobes protein (gene sol), a neuronal protein that contains a calpain-like domain. - Yeast thiol protease BLH1/YCP1/LAP3. - Caenorhabditis elegans hypothetical protein C06G4.2, a calpain-like protein. Two bacterial peptidases are also part of this family: - Aminopeptidase C from Lactococcus lactis (gene pepC) [5]. - Thiol protease tpr from Porphyromonas gingivalis. Three other proteins are structurally related to this family, but may have lost their proteolytic activity. - Soybean oil body protein P34. This protein has its active site cysteine replaced by a glycine. - Rat testin, a sertoli cell secretory protein highly similar to cathepsin L but with the active site cysteine is replaced by a serine. Rat testin should not be confused with mouse testin which is a LIM-domain protein (see ). - Plasmodium falciparum serine-repeat protein (SERA), the major blood stage antigen. This protein of 111 Kd possesses a C-terminal thiol-protease-like domain [6], but the active site cysteine is replaced by a serine. The sequences around the three active site residues are well conserved and can be used as signature patterns. -Consensus pattern: Q-{V}-x-{DE}-[GE]-{F}-C-[YW]-{DN}-x-[STAGC]-[STAGCV] [C is the active site residue] -Sequences known to belong to this class detected by the pattern: ALL, except for P34, testins, SERA antigen, and Theileria annulara protease. -Other sequence(s) detected in Swiss-Prot: 6. -Note: The residue in position 4 of the pattern is almost always cysteine; the only exceptions are calpains (Leu), bleomycin hydrolase (Ser) and yeast YCP1 (Ser). -Note: The residue in position 5 of the pattern is always Gly except in papaya protease IV where it is Glu. -Consensus pattern: [LIVMGSTAN]-{IEVK}-H-[GSACE]-[LIVM]-{GPSI}-[LIVMAT](2)-G- {SLAG}-[GSADNH] [H is the active site residue] -Sequences known to belong to this class detected by the pattern: ALL, except for calpains, P34 and tpr. -Other sequence(s) detected in Swiss-Prot: 146. -Consensus pattern: [FYCH]-[WI]-[LIVT]-x-[KRQAG]-N-[ST]-W-x(3)-[FYW]-G-x(2)-G- [LFYW]-[LIVMFYG]-x-[LIVMF] [N is the active site residue] -Sequences known to belong to this class detected by the pattern: ALL, except for calpains, bromelain, yeast BLH1, tomato low-temperature induced protease, cathepsin O, pepC and tpr. -Other sequence(s) detected in Swiss-Prot: NONE. -Note: These proteins belong to family C1 (papain-type) and C2 (calpains) in the classification of peptidases [7,E1]. -Expert(s) to contact by email: Turk B.; boris.turk@ijs.si -Last update: April 2006 / Patterns revised. [ 1] Dufour E. "Sequence homologies, hydrophobic profiles and secondary structures of cathepsins B, H and L: comparison with papain and actinidin." Biochimie 70:1335-1342(1988). PubMed=3148320 [ 2] Kirschke H., Barrett A.J., Rawlings N.D. Protein Prof. 2:1587-1643(1995). [ 3] Shi G.-P., Chapman H.A., Bhairi S.M., DeLeeuw C., Reddy V.Y., Weiss S.J. "Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2." FEBS Lett. 357:129-134(1995). PubMed=7805878 [ 4] Velasco G., Ferrando A.A., Puente X.S., Sanchez L.M., Lopez-Otin C. "Human cathepsin O. Molecular cloning from a breast carcinoma, production of the active enzyme in Escherichia coli, and expression analysis in human tissues." J. Biol. Chem. 269:27136-27142(1994). PubMed=7929457 [ 5] Chapot-Chartier M.P., Nardi M., Chopin M.C., Chopin A., Gripon J.C. Appl. Environ. Microbiol. 59:330-333(1993). [ 6] Higgins D.G., McConnell D.J., Sharp P.M. "Malarial proteinase?" Nature 340:604-604(1989). PubMed=2671749; DOI=10.1038/340604a0 [ 7] Rawlings N.D., Barrett A.J. "Families of cysteine peptidases." Methods Enzymol. 244:461-486(1994). PubMed=7845226 [E1] https://www.uniprot.org/docs/peptidas -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}