Prosite Database

PDOC00126

{PDOC00126}
{PS00139; THIOL_PROTEASE_CYS}
{PS00639; THIOL_PROTEASE_HIS}
{PS00640; THIOL_PROTEASE_ASN}
{BEGIN}
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* Eukaryotic thiol (cysteine) proteases active sites *
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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 3.4.22.17).   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-x(3)-[GE]-x-C-[YW]-x(2)-[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: 4.

-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]-x-H-[GSACE]-[LIVM]-x-[LIVMAT](2)-G-x-[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: 102.

-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: November 1997 / Text revised.

[ 1] Dufour E.
     Biochimie 70:1335-1342(1988).
[ 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.
     FEBS Lett. 357:129-134(1995).
[ 4] Velasco G., Ferrando A.A., Puente X.S., Sanchez L.M., Lopez-Otin C.
     J. Biol. Chem. 269:27136-27142(1994).
[ 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.
     Nature 340:604-604(1989).
[ 7] Rawlings N.D., Barrett A.J.
     Meth. Enzymol. 244:461-486(1994).
[E1] http://www.expasy.ch/cgi-bin/lists?peptidas.txt