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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 α, β, and γ; 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 <PDOC00382>).
• 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.

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).

The residue in position 5 of the pattern is always Gly except in papaya protease IV where it is Glu.

[LIVMGSTAN]-{IEVK}-H-[GSACE]-[LIVM]-{GPSI}-[LIVMAT](2)-G- {SLAG}-[GSADNH] [H is the active site residue]

ALL, except for calpains, P34 and tpr.

146.

[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]

ALL, except for calpains, bromelain, yeast BLH1, tomato low-temperature induced protease, cathepsin O, pepC and tpr.

NONE.

These proteins belong to family C1 (papain-type) and C2 (calpains) in the classification of peptidases [7,E1].

Turk B.

April 2006 / Patterns revised.

PROSITE methods (with tools and information) covered by this documentation:

THIOL_PROTEASE_ASN, PS00640; Eukaryotic thiol (cysteine) proteases asparagine active site  (PATTERN)

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00640 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00640 • Scan Swiss-Prot/TrEMBL entries against PS00640 • view ligand binding statistics

Matching PDB structures: 1AEC 1AIM 1ATK 1AU0 ... [ALL]

THIOL_PROTEASE_CYS, PS00139; Eukaryotic thiol (cysteine) proteases cysteine active site  (PATTERN)

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.

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00139 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00139 • Scan Swiss-Prot/TrEMBL entries against PS00139 • view ligand binding statistics

Matching PDB structures: 1AEC 1AIM 1ATK 1AU0 ... [ALL]

THIOL_PROTEASE_HIS, PS00639; Eukaryotic thiol (cysteine) proteases histidine active site  (PATTERN)

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00639 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00639 • Scan Swiss-Prot/TrEMBL entries against PS00639 • view ligand binding statistics

Matching PDB structures: 1A6R 1AEC 1AIM 1ATK ... [ALL]

1	Authors	Dufour E.
	Title	Sequence homologies, hydrophobic profiles and secondary structures of cathepsins B, H and L: comparison with papain and actinidin.
	Source	Biochimie 70:1335-1342(1988).
	PubMed ID	3148320

2	Authors	Kirschke H., Barrett A.J., Rawlings N.D.
	Source	Protein Prof. 2:1587-1643(1995).

3	Authors	Shi G.-P., Chapman H.A., Bhairi S.M., DeLeeuw C., Reddy V.Y., Weiss S.J.
	Title	Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2.
	Source	FEBS Lett. 357:129-134(1995).
	PubMed ID	7805878

4	Authors	Velasco G., Ferrando A.A., Puente X.S., Sanchez L.M., Lopez-Otin C.
	Title	Human cathepsin O. Molecular cloning from a breast carcinoma, production of the active enzyme in Escherichia coli, and expression analysis in human tissues.
	Source	J. Biol. Chem. 269:27136-27142(1994).
	PubMed ID	7929457

5	Authors	Chapot-Chartier M.P., Nardi M., Chopin M.C., Chopin A., Gripon J.C.
	Source	Appl. Environ. Microbiol. 59:330-333(1993).

6	Authors	Higgins D.G., McConnell D.J., Sharp P.M.
	Title	Malarial proteinase?
	Source	Nature 340:604-604(1989).
	PubMed ID	2671749
	DOI	10.1038/340604a0

7	Authors	Rawlings N.D., Barrett A.J.
	Title	Families of cysteine peptidases.
	Source	Methods Enzymol. 244:461-486(1994).
	PubMed ID	7845226

E1
Source	http://www.uniprot.org/docs/peptidas

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