test_prodoc PDOC00100 prosite_refs ('PS00107', 'PROTEIN_KINASE_ATP') ('PS00108', 'PROTEIN_KINASE_ST') ('PS00109', 'PROTEIN_KINASE_TYR') ('PS50011', 'PROTEIN_KINASE_DOM') ****************************************** * Protein kinases signatures and profile * ****************************************** Eukaryotic protein kinases [1 to 5] are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. We have selected two of these regions to build signature patterns. The first region, which is located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. The second region, which is located in the central part of the catalytic domain, contains a conserved aspartic acid residue which is important for the catalytic activity of the enzyme [6]; we have derived two signature patterns for that region: one specific for serine/ threonine kinases and the other for tyrosine kinases. We also developed a profile which is based on the alignment in [1] and covers the entire catalytic domain. -Consensus pattern: [LIV]-G-{P}-G-{P}-[FYWMGSTNH]-[SGA]-{PW}-[LIVCAT]-{PD}-x- [GSTACLIVMFY]-x(5,18)-[LIVMFYWCSTAR]-[AIVP]-[LIVMFAGCKR]-K [K binds ATP] -Sequences known to belong to this class detected by the pattern: the majority of known protein kinases but it fails to find a number of them, especially viral kinases which are quite divergent in this region and are completely missed bythis pattern. -Other sequence(s) detected in SWISS-PROT: 35. -Consensus pattern: [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-K-x(2)-N-[LIVMFYCT](3) [D is an active site residue] -Sequences known to belong to this class detected by the pattern: Most serine/ threonine specific protein kinases with 10 exceptions (half of them viral kinases) and also Epstein-Barr virus BGLF4 and Drosophila ninaC which have respectively Ser and Arg instead of the conserved Lys and which are therefore detected by the tyrosine kinase specific pattern described below. -Other sequence(s) detected in SWISS-PROT: 1. -Consensus pattern: [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-[RSTAC]-x(2)-N-[LIVMFYC](3) [D is an active site residue] -Sequences known to belong to this class detected by the pattern: ALL tyrosine specific protein kinases with the exception of human ERBB3 and mouse blk. This pattern will also detect most bacterial aminoglycoside phosphotransferases [8,9] and herpesviruses ganciclovir kinases [10]; which are proteins structurally and evolutionary related to protein kinases. -Other sequence(s) detected in SWISS-PROT: 15. -Sequences known to belong to this class detected by the profile: ALL, except for three viral kinases. This profile also detects receptor guanylate cyclases (see ) and 2-5A-dependent ribonucleases. Sequence similarities between these two families and the eukaryotic protein kinase family have been noticed before. It also detects Arabidopsis thaliana kinase- like protein TMKL1 which seems to have lost its catalytic activity. -Other sequence(s) detected in SWISS-PROT: 4. -Note: if a protein analyzed includes the two protein kinase signatures, the probability of it being a protein kinase is close to 100% -Note: eukaryotic-type protein kinases have also been found in prokaryotes such as Myxococcus xanthus [11] and Yersinia pseudotuberculosis. -Note: the patterns shown above has been updated since their publication in [7]. -Note: this documentation entry is linked to both signature patterns and a profile. As the profile is much more sensitive than the patterns, you should use it if you have access to the necessary software tools to do so. -Expert(s) to contact by email: Hunter T.; hunter@salk-sc2.sdsc.edu Quinn A.M.; quinn@biomed.med.yale.edu -Last update: November 1995 / Patterns and text revised; profile added. references 1 Hanks S.K., Hunter T. FASEB J. 9:576-596(1995). 2 Hunter T. Meth. Enzymol. 200:3-37(1991). 3 Hanks S.K., Quinn A.M. Meth. Enzymol. 200:38-62(1991). 4 Hanks S.K. Curr. Opin. Struct. Biol. 1:369-383(1991). 5 Hanks S.K., Quinn A.M., Hunter T. Science 241:42-52(1988). 6 Knighton D.R., Zheng J., Ten Eyck L.F., Ashford V.A., Xuong N.-H., Taylor S.S., Sowadski J.M. Science 253:407-414(1991). 7 Bairoch A., Claverie J.-M. Nature 331:22(1988). 8 Benner S. Nature 329:21-21(1987). 9 Kirby R. J. Mol. Evol. 30:489-492(1992). 10 Littler E., Stuart A.D., Chee M.S. Nature 358:160-162(1992). 11 Munoz-Dorado J., Inouye S., Inouye M. Cell 67:995-1006(1991). PDOC00113 prosite_refs ('PS00123', 'ALKALINE_PHOSPHATASE') ************************************ * Alkaline phosphatase active site * ************************************ Alkaline phosphatase (EC 3.1.3.1) (ALP) [1] is a zinc and magnesium-containing metalloenzyme which hydrolyzes phosphate esters, optimally at high pH. It is found in nearly all living organisms, with the exception of some plants. In Escherichia coli, ALP (gene phoA) is found in the periplasmic space. In yeast it (gene PHO8) is found in lysosome-like vacuoles and in mammals, it is a glycoprotein attached to the membrane by a GPI-anchor. In mammals, four different isozymes are currently known [2]. Three of them are tissue-specific: the placental, placental-like (germ cell) and intestinal isozymes. The fourth form is tissue non-specific and was previously known as the liver/bone/kidney isozyme. Streptomyces' species involved in the synthesis of streptomycin (SM), an antibiotic, express a phosphatase (EC 3.1.3.39) (gene strK) which is highly related to ALP. It specifically cleaves both streptomycin-6-phosphate and, more slowly, streptomycin-3"-phosphate. A serine is involved in the catalytic activity of ALP. The region around the active site serine is relatively well conserved and can be used as a signature pattern. -Consensus pattern: [IV]-x-D-S-[GAS]-[GASC]-[GAST]-[GA]-T [S is the active site residue] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in SWISS-PROT: 3. -Last update: June 1994 / Text revised. references 1 Trowsdale J., Martin D., Bicknell D., Campbell I. Biochem. Soc. Trans. 18:178-180(1990). 2 Manes T., Glade K., Ziomek C.A., Millan J.L. Genomics 8:541-554(1990). 3 Mansouri K., Piepersberg W. Mol. Gen. Genet. 228:459-469(1991). PDOC00144 prosite_refs ('PS00159', 'ALDOLASE_KDPG_KHG_1') ('PS00160', 'ALDOLASE_KDPG_KHG_2') ************************************************* * KDPG and KHG aldolases active site signatures * ************************************************* 4-hydroxy-2-oxoglutarate aldolase (EC 4.1.3.16) (KHG-aldolase) catalyzes the interconversion of 4-hydroxy-2-oxoglutarate into pyruvate and glyoxylate. Phospho-2-dehydro-3-deoxygluconate aldolase (EC 4.1.2.14) (KDPG-aldolase) catalyzes the interconversion of 6-phospho-2-dehydro-3-deoxy-D-gluconate into pyruvate and glyceraldehyde 3-phosphate. These two enzymes are structurally and functionally related [1]. They are both homotrimeric proteins of approximately 220 amino-acid residues. They are class I aldolases whose catalytic mechanism involves the formation of a Schiff-base intermediate between the substrate and the epsilon-amino group of a lysine residue. In both enzymes, an arginine is required for catalytic activity. We developed two signature patterns for these enzymes. The first one contains the active site arginine and the second, the lysine involved in the Schiff- base formation. -Consensus pattern: G-[LIVM]-x(3)-E-[LIV]-T-[LF]-R [R is the active site residue] -Sequences known to belong to this class detected by the pattern: ALL, except for Bacillus subtilis KDPG-aldolase which has Thr instead of Arg in the active site. -Other sequence(s) detected in SWISS-PROT: NONE. -Consensus pattern: G-x(3)-[LIVMF]-K-[LF]-F-P-[SA]-x(3)-G [K is involved in Schiff-base formation] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in SWISS-PROT: NONE. -Last update: November 1997 / Patterns and text revised. references 1 Vlahos C J., Dekker E.E. J. Biol. Chem. 263:11683-11691(1988). PDOC00149 prosite_refs ('PS00165', 'DEHYDRATASE_SER_THR') ********************************************************************** * Serine/threonine dehydratases pyridoxal-phosphate attachment site * ********************************************************************** Serine and threonine dehydratases [1,2] are functionally and structurally related pyridoxal-phosphate dependent enzymes: - L-serine dehydratase (EC 4.2.1.13) and D-serine dehydratase (EC 4.2.1.14) catalyze the dehydratation of L-serine (respectively D-serine) into ammonia and pyruvate. - Threonine dehydratase (EC 4.2.1.16) (TDH) catalyzes the dehydratation of threonine into alpha-ketobutarate and ammonia. In Escherichia coli and other microorganisms, two classes of TDH are known to exist. One is involved in the biosynthesis of isoleucine, the other in hydroxamino acid catabolism. Threonine synthase (EC 4.2.99.2) is also a pyridoxal-phosphate enzyme, it catalyzes the transformation of homoserine-phosphate into threonine. It has been shown [3] that threonine synthase is distantly related to the serine/ threonine dehydratases. In all these enzymes, the pyridoxal-phosphate group is attached to a lysine residue. The sequence around this residue is sufficiently conserved to allow the derivation of a pattern specific to serine/threonine dehydratases and threonine synthases. -Consensus pattern: [DESH]-x(4,5)-[STVG]-x-[AS]-[FYI]-K-[DLIFSA]-[RVMF]-[GA]- [LIVMGA] [The K is the pyridoxal-P attachment site] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in SWISS-PROT: 12. -Note: some bacterial L-serine dehydratases - such as those from Escherichia coli - are iron-sulfur proteins [4] and do not belong to this family. -Last update: November 1995 / Pattern and text revised. references 1 Ogawa H., Gomi T., Konishi K., Date T., Naakashima H., Nose K., Matsuda Y., Peraino C., Pitot H.C., Fujioka M. J. Biol. Chem. 264:15818-15823(1989). 2 Datta P., Goss T.J., Omnaas J.R., Patil R.V. Proc. Natl. Acad. Sci. U.S.A. 84:393-397(1987). 3 Parsot C. EMBO J. 5:3013-3019(1986). 4 Grabowski R., Hofmeister A.E.M., Buckel W. Trends Biochem. Sci. 18:297-300(1993). PDOC00340 prosite_refs ('PS00406', 'ACTINS_1') ('PS00432', 'ACTINS_2') ('PS01132', 'ACTINS_ACT_LIKE') ********************* * Actins signatures * ********************* Actins [1 to 4] are highly conserved contractile proteins that are present in all eukaryotic cells. In vertebrates there are three groups of actin isoforms: alpha, beta and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co- exists in most cell types as components of the cytoskeleton and as mediators of internal cell motility. In plants [5] there are many isoforms which are probably involved in a variety of functions such as cytoplasmic streaming, cell shape determination, tip growth, graviperception, cell wall deposition, etc. Actin exists either in a monomeric form (G-actin) or in a polymerized form (F- actin). Each actin monomer can bind a molecule of ATP; when polymerization occurs, the ATP is hydrolyzed. Actin is a protein of from 374 to 379 amino acid residues. The structure of actin has been highly conserved in the course of evolution. Recently some divergent actin-like proteins have been identified in several species. These proteins are: - Centractin (actin-RPV) from mammals, fungi (yeast ACT5, Neurospora crassa ro-4) and Pneumocystis carinii (actin-II). Centractin seems to be a component of a multi-subunit centrosomal complex involved in microtubule based vesicle motility. This subfamily is also known as ARP1. - ARP2 subfamily which includes chicken ACTL, yeast ACT2, Drosophila 14D, C.elegans actC. - ARP3 subfamily which includes actin 2 from mammals, Drosophila 66B, yeast ACT4 and fission yeast act2. - ARP4 subfamily which includes yeast ACT3 and Drosophila 13E. We developed three signature patterns. The first two are specific to actins and span positions 54 to 64 and 357 to 365. The last signature picks up both actins and the actin-like proteins and corresponds to positions 106 to 118 in actins. -Consensus pattern: [FY]-[LIV]-G-[DE]-E-A-Q-x-[RKQ](2)-G -Sequences known to belong to this class detected by the pattern: ALL, except for the actin-like proteins and 10 actins. -Other sequence(s) detected in SWISS-PROT: NONE. -Consensus pattern: W-[IV]-[STA]-[RK]-x-[DE]-Y-[DNE]-[DE] -Sequences known to belong to this class detected by the pattern: ALL, except for the actin-like proteins and 9 actins. -Other sequence(s) detected in SWISS-PROT: NONE. -Consensus pattern: [LM]-[LIVM]-T-E-[GAPQ]-x-[LIVMFYWHQ]-N-[PSTAQ]-x(2)-N-[KR] -Sequences known to belong to this class detected by the pattern: ALL, except for 5 actins. -Other sequence(s) detected in SWISS-PROT: NONE. -Last update: November 1997 / Text revised. references 1 Sheterline P., Clayton J., Sparrow J.C. (In) Actins, 3rd Edition, Academic Press Ltd, London, (1996). 2 Pollard T.D., Cooper J.A. Annu. Rev. Biochem. 55:987-1036(1986). 3 Pollard T.D. Curr. Opin. Cell Biol. 1:33-40(1990). 4 Rubenstein P.A. BioEssays 12:309-315(1990). 5 Meagher R.B., McLean B.G. Cell Motil. Cytoskeleton 16:164-166(1990). PDOC00424 prosite_refs ('PS00488', 'PAL_HISTIDASE') ********************************************************** * Phenylalanine and histidine ammonia-lyases active site * ********************************************************** Phenylalanine ammonia-lyase (EC 4.3.1.5) (PAL) is a key enzyme of plant and fungi phenylpropanoid metabolism which is involved in the biosynthesis of a wide variety of secondary metabolites such as flavanoids, furanocoumarin phytoalexins and cell wall components. These compounds have many important roles in plants during normal growth and in responses to environmental stress. PAL catalyzes the removal of an ammonia group from phenylalanine to form trans-cinnamate. Histidine ammonia-lyase (EC 4.3.1.3) (histidase) catalyzes the first step in histidine degradation, the removal of an ammonia group from histidine to produce urocanic acid. The two types of enzymes are functionally and structurally related [1]. They are the only enzymes which are known to have the modified amino acid dehydro- alanine (DHA) in their active site. A serine residue has been shown [2,3,4] to be the precursor of this essential electrophilic moiety. The region around this active site residue is well conserved and can be used as a signature pattern. -Consensus pattern: G-[STG]-[LIVM]-[STG]-[AC]-S-G-[DH]-L-x-P-L-[SA]-x(2)-[SA] [S is the active site residue] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in SWISS-PROT: NONE. -Last update: November 1995 / Pattern and text revised. references 1 Taylor R.G., Lambert M.A., Sexsmith E., Sadler S.J., Ray P.N., Mahuran D.J., McInnes R.R. J. Biol. Chem. 265:18192-18199(1990). 2 Langer M., Reck G., Reed J., Retey J. Biochemistry 33:6462-6467(1994). 3 Schuster B., Retey J. FEBS Lett. 349:252-254(1994). 4 Taylor R.G., McInnes R.R. J. Biol. Chem. 269:27473-27477(1994). PDOC00472 prosite_refs ('PS00546', 'CYSTEINE_SWITCH') ***************************** * Matrixins cysteine switch * ***************************** Mammalian extracellular matrix metalloproteinases (EC 3.4.24.-), also known as matrixins [1] (see ), are zinc-dependent enzymes. They are secreted by cells in an inactive form (zymogen) that differs from the mature enzyme by the presence of an N-terminal propeptide. A highly conserved octapeptide is found two residues downstream of the C-terminal end of the propeptide. This region has been shown to be involved in autoinhibition of matrixins [2,3]; a cysteine within the octapeptide chelates the active site zinc ion, thus inhibiting the enzyme. This region has been called the 'cysteine switch' or 'autoinhibitor region'. A cysteine switch has been found in the following zinc proteases: - MMP-1 (EC 3.4.24.7) (interstitial collagenase). - MMP-2 (EC 3.4.24.24) (72 Kd gelatinase). - MMP-3 (EC 3.4.24.17) (stromelysin-1). - MMP-7 (EC 3.4.24.23) (matrilysin). - MMP-8 (EC 3.4.24.34) (neutrophil collagenase). - MMP-9 (EC 3.4.24.35) (92 Kd gelatinase). - MMP-10 (EC 3.4.24.22) (stromelysin-2). - MMP-11 (EC 3.4.24.-) (stromelysin-3). - MMP-12 (EC 3.4.24.65) (macrophage metalloelastase). - MMP-13 (EC 3.4.24.-) (collagenase 3). - MMP-14 (EC 3.4.24.-) (membrane-type matrix metalliproteinase 1). - MMP-15 (EC 3.4.24.-) (membrane-type matrix metalliproteinase 2). - MMP-16 (EC 3.4.24.-) (membrane-type matrix metalliproteinase 3). - Sea urchin hatching enzyme (EC 3.4.24.12) (envelysin) [4]. - Chlamydomonas reinhardtii gamete lytic enzyme (GLE) [5]. -Consensus pattern: P-R-C-[GN]-x-P-[DR]-[LIVSAPKQ] [C chelates the zinc ion] -Sequences known to belong to this class detected by the pattern: ALL, except for cat MMP-7 and mouse MMP-11. -Other sequence(s) detected in SWISS-PROT: NONE. -Last update: November 1997 / Pattern and text revised. references 1 Woessner J. Jr. FASEB J. 5:2145-2154(1991). 2 Sanchez-Lopez R., Nicholson R., Gesnel M.C., Matrisian L.M., Breathnach R. J. Biol. Chem. 263:11892-11899(1988). 3 Park A.J., Matrisian L.M., Kells A.F., Pearson R., Yuan Z., Navre M. J. Biol. Chem. 266:1584-1590(1991). 4 Lepage T., Gache C. EMBO J. 9:3003-3012(1990). 5 Kinoshita T., Fukuzawa H., Shimada T., Saito T., Matsuda Y. Proc. Natl. Acad. Sci. U.S.A. 89:4693-4697(1992). PDOC00640 prosite_refs ('PS00812', 'GLYCOSYL_HYDROL_F8') ****************************************** * Glycosyl hydrolases family 8 signature * ****************************************** The microbial degradation of cellulose and xylans requires several types of enzymes such as endoglucanases (EC 3.2.1.4), cellobiohydrolases (EC 3.2.1.91) (exoglucanases), or xylanases (EC 3.2.1.8) [1,2]. Fungi and bacteria produces a spectrum of cellulolytic enzymes (cellulases) and xylanases which, on the basis of sequence similarities, can be classified into families. One of these families is known as the cellulase family D [3] or as the glycosyl hydrolases family 8 [4,E1]. The enzymes which are currently known to belong to this family are listed below. - Acetobacter xylinum endonuclease cmcAX. - Bacillus strain KSM-330 acidic endonuclease K (Endo-K). - Cellulomonas josui endoglucanase 2 (celB). - Cellulomonas uda endoglucanase. - Clostridium cellulolyticum endoglucanases C (celcCC). - Clostridium thermocellum endoglucanases A (celA). - Erwinia chrysanthemi minor endoglucanase y (celY). - Bacillus circulans beta-glucanase (EC 3.2.1.73). - Escherichia coli hypothetical protein yhjM. The most conserved region in these enzymes is a stretch of about 20 residues that contains two conserved aspartate. The first asparatate is thought [5] to act as the nucleophile in the catalytic mechanism. We have used this region as a signature pattern. -Consensus pattern: A-[ST]-D-[AG]-D-x(2)-[IM]-A-x-[SA]-[LIVM]-[LIVMG]-x-A- x(3)-[FW] [The first D is an active site residue] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in SWISS-PROT: NONE. -Expert(s) to contact by email: Henrissat B.; bernie@afmb.cnrs-mrs.fr -Last update: November 1997 / Text revised. references 1 Beguin P. Annu. Rev. Microbiol. 44:219-248(1990). 2 Gilkes N.R., Henrissat B., Kilburn D.G., Miller R.C. Jr., Warren R.A.J. Microbiol. Rev. 55:303-315(1991). 3 Henrissat B., Claeyssens M., Tomme P., Lemesle L., Mornon J.-P. Gene 81:83-95(1989). 4 Henrissat B. Biochem. J. 280:309-316(1991). 5 Alzari P.M., Souchon H., Dominguez R. Structure 4:265-275(1996). E1 http://www.expasy.ch/cgi-bin/lists?glycosid.txt PDOC00787 prosite_refs ('PS01027', 'GLYCOSYL_HYDROL_F39') ****************************************************** * Glycosyl hydrolases family 39 putative active site * ****************************************************** It has been shown [1,E1] that the following glycosyl hydrolases can be classified into a single family on the basis of sequence similarities: - Mammalian lysosomal alpha-L-iduronidase (EC 3.2.1.76). - Caldocellum saccharolyticum and Thermoanaerobacter saccharolyticum beta- xylosidase (EC 3.2.1.37) (gene xynB). The best conserved regions in these enzymes is located in the N-terminal section. It contains a glutamic acid residue which, on the basis of similarities with other families of glycosyl hydrolases [2], probably acts as the proton donor in the catalytic mechanism. We use this region as a signature pattern. -Consensus pattern: W-x-F-E-x-W-N-E-P-[DN] [The second E is the putative active site residue] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in SWISS-PROT: NONE. -Expert(s) to contact by email: Henrissat B.; bernie@afmb.cnrs-mrs.fr -Last update: November 1997 / Text revised. references 1 Henrissat B., Bairoch A. Biochem. J. 293:781-788(1993). 2 Henrissat B., Callebaut I., Fabrega S., Lehn P., Mornon J.-P., Davies G. Proc. Natl. Acad. Sci. U.S.A. 92:7090-7094(1995). E1 http://www.expasy.ch/cgi-bin/lists?glycosid.txt PDOC00933 prosite_refs ('PS01213', 'GLOBIN_FAM_2') ********************************************** * Protozoan/cyanobacterial globins signature * ********************************************** Globins are heme-containing proteins involved in binding and/or transporting oxygen [1]. Almost all globins belong to a large family (see ), the only exceptions are the following proteins which form a family of their own [2,3]: - Monomeric hemoglobins from the protozoan Paramecium caudatum, Tetrahymena pyriformis and Tetrahymena thermophila. - Cyanoglobin from the cyanobacteria Nostoc commune. - Globins LI637 and LI410 from the chloroplast of the alga Chlamydomonas eugametos. - Mycobacterium tuberculosis hypothetical protein MtCY48.23. These proteins contain a conserved histidine which could be involved in heme- binding. As a signature pattern, we use a conserved region that ends with this residue. -Consensus pattern: F-[LF]-x(5)-G-[PA]-x(4)-G-[KRA]-x-[LIVM]-x(3)-H -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in SWISS-PROT: NONE. -Last update: November 1997 / First entry. references 1 Concise Encyclopedia Biochemistry, Second Edition, Walter de Gruyter, Berlin New-York (1988). 2 Takagi T. Curr. Opin. Struct. Biol. 3:413-418(1993). 3 Couture M., Chamberland H., St-Pierre B., Lafontaine J., Guertin M.; Mol. Gen. Genet. 243:185-197(1994).