ID PPGB_HUMAN Reviewed; 480 AA. AC P10619; B2R798; Q561W6; Q5JZH1; Q96KJ2; Q9BR08; Q9BW68; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 16-APR-2002, sequence version 2. DT 16-OCT-2013, entry version 169. DE RecName: Full=Lysosomal protective protein; DE EC=3.4.16.5; DE AltName: Full=Carboxypeptidase C; DE AltName: Full=Carboxypeptidase L; DE AltName: Full=Cathepsin A; DE AltName: Full=Protective protein cathepsin A; DE Short=PPCA; DE AltName: Full=Protective protein for beta-galactosidase; DE Contains: DE RecName: Full=Lysosomal protective protein 32 kDa chain; DE Contains: DE RecName: Full=Lysosomal protective protein 20 kDa chain; DE Flags: Precursor; GN Name=CTSA; Synonyms=PPGB; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RX PubMed=3136930; DOI=10.1016/S0092-8674(88)90999-3; RA Galjart N.J., Gillemans N., Harris A., van de Horst G.T.J., RA Verheijen F.W., Galjaard H., D'Azzo A.; RT "Expression of cDNA encoding the human 'protective protein' associated RT with lysosomal beta-galactosidase and neuraminidase: homology to yeast RT proteases."; RL Cell 54:755-764(1988). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., RA Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta, and Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP PROTEIN SEQUENCE OF 29-53 AND 327-351. RC TISSUE=Platelet; RX PubMed=1694176; RA Jackman H.L., Tan F., Tamei H., Beurling-Harbury C., Li X.-Y., RA Skidgel R.A., Erdoes E.G.; RT "A peptidase in human platelets that deamidates tachykinins. Probable RT identity with the lysosomal 'protective protein'."; RL J. Biol. Chem. 265:11265-11272(1990). RN [6] RP PROTEIN SEQUENCE OF 29-37. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., RA Thomas G.R., Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass RT spectrometric identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [7] RP FUNCTION, AND MUTAGENESIS. RX PubMed=1907282; RA Galjart N.J., Morreau H., Willemsen R., Gillemans N., Bonten E.J., RA D'Azzo A.; RT "Human lysosomal protective protein has cathepsin A-like activity RT distinct from its protective function."; RL J. Biol. Chem. 266:14754-14762(1991). RN [8] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-145, AND MASS RP SPECTROMETRY. RC TISSUE=Platelet; RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200; RA Lewandrowski U., Moebius J., Walter U., Sickmann A.; RT "Elucidation of N-glycosylation sites on human platelet proteins: a RT glycoproteomic approach."; RL Mol. Cell. Proteomics 5:226-233(2006). RN [9] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-145 AND ASN-333, AND MASS RP SPECTROMETRY. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of RT multiple enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS). RX PubMed=8591035; DOI=10.1016/S0969-2126(01)00260-X; RA Rudenko G., Bonten E., D'Azzo A., Hol W.G.J.; RT "Three-dimensional structure of the human 'protective protein': RT structure of the precursor form suggests a complex activation RT mechanism."; RL Structure 3:1249-1259(1995). RN [12] RP VARIANT GSL VAL-440. RX PubMed=1756715; RA Zhou X.Y., Galjart N.J., Willemsen R., Gillemans N., Galjaard H., RA D'Azzo A.; RT "A mutation in a mild form of galactosialidosis impairs dimerization RT of the protective protein and renders it unstable."; RL EMBO J. 10:4041-4048(1991). RN [13] RP VARIANTS GSL ARG-49; ARG-65; LEU-90; ASN-249 AND CYS-395. RX PubMed=8514852; DOI=10.1172/JCI116472; RA Shimmoto M., Fukuhara Y., Itoh K., Oshima A., Sakuraba H., Suzuki Y.; RT "Protective protein gene mutations in galactosialidosis."; RL J. Clin. Invest. 91:2393-2398(1993). RN [14] RP VARIANTS GSL TYR-51; MET-132; PRO-236; ASN-249; THR-406; SER-439 AND RP VAL-440. RX PubMed=8968752; DOI=10.1093/hmg/5.12.1977; RA Zhou X.Y., van der Spoel A., Rottier R., Hale G., Willemsen R., RA Berry G.T., Strisciuglio P., Morrone A., Zammarchi E., Andria G., RA d'Azzo A.; RT "Molecular and biochemical analysis of protective protein/cathepsin A RT mutations: correlation with clinical severity in galactosialidosis."; RL Hum. Mol. Genet. 5:1977-1987(1996). RN [15] RP VARIANT GSL GLU-453. RX PubMed=10944848; DOI=10.1007/s100380070027; RA Takiguchi K., Itoh K., Shimmoto M., Ozand P.T., Doi H., Sakuraba H.; RT "Structural and functional study of K453E mutant protective RT protein/cathepsin A causing the late infantile form of RT galactosialidosis."; RL J. Hum. Genet. 45:200-206(2000). CC -!- FUNCTION: Protective protein appears to be essential for both the CC activity of beta-galactosidase and neuraminidase, it associates CC with these enzymes and exerts a protective function necessary for CC their stability and activity. This protein is also a CC carboxypeptidase and can deamidate tachykinins. CC -!- CATALYTIC ACTIVITY: Release of a C-terminal amino acid with broad CC specificity. CC -!- SUBUNIT: Heterodimer of a 32 kDa chain and a 20 kDa chain; CC disulfide-linked. CC -!- SUBCELLULAR LOCATION: Lysosome. CC -!- DISEASE: Galactosialidosis (GSL) [MIM:256540]: A lysosomal storage CC disease associated with a combined deficiency of beta- CC galactosidase and neuraminidase, secondary to a defect in CC cathepsin A. All patients have clinical manifestations typical of CC a lysosomal disorder, such as coarse facies, cherry red spots, CC vertebral changes, foam cells in the bone marrow, and vacuolated CC lymphocytes. Three phenotypic subtypes are recognized. The early CC infantile form is associated with fetal hydrops, edema, ascites, CC visceromegaly, skeletal dysplasia, and early death. The late CC infantile type is characterized by hepatosplenomegaly, growth CC retardation, cardiac involvement, and a normal or mildly affected CC mental state. The juvenile/adult form is characterized by CC myoclonus, ataxia, angiokeratoma, mental retardation, neurologic CC deterioration, absence of visceromegaly, and long survival. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase S10 family. CC -!- SEQUENCE CAUTION: CC Sequence=CAI20248.1; Type=Erroneous initiation; CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CTSA"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M22960; AAA36476.1; -; mRNA. DR EMBL; AK312898; BAG35745.1; -; mRNA. DR EMBL; AL008726; CAA15501.1; -; Genomic_DNA. DR EMBL; AL008726; CAI20248.1; ALT_INIT; Genomic_DNA. DR EMBL; BC000597; AAH00597.1; -; mRNA. DR EMBL; BC093009; AAH93009.1; -; mRNA. DR IPI; IPI00021794; -. DR PIR; A31589; A31589. DR RefSeq; NP_000299.2; NM_000308.2. DR RefSeq; NP_001121167.1; NM_001127695.1. DR RefSeq; NP_001161066.1; NM_001167594.1. DR UniGene; Hs.609336; -. DR PDB; 1IVY; X-ray; 2.20 A; A/B=29-480. DR PDB; 3BP4; X-ray; 1.85 A; C=2-10. DR PDB; 3BP7; X-ray; 1.80 A; C=2-10. DR PDB; 3BXN; X-ray; 1.86 A; C=2-10. DR PDB; 4AZ0; X-ray; 2.17 A; A=29-326, B=327-480. DR PDB; 4AZ3; X-ray; 2.04 A; A=29-326, B=327-480. DR PDBsum; 1IVY; -. DR PDBsum; 3BP4; -. DR PDBsum; 3BP7; -. DR PDBsum; 3BXN; -. DR PDBsum; 4AZ0; -. DR PDBsum; 4AZ3; -. DR ProteinModelPortal; P10619; -. DR SMR; P10619; 29-480. DR IntAct; P10619; 8. DR MINT; MINT-3007366; -. DR STRING; 9606.ENSP00000361562; -. DR MEROPS; S10.002; -. DR PhosphoSite; P10619; -. DR DMDM; 20178316; -. DR OGP; P10619; -. DR PaxDb; P10619; -. DR PRIDE; P10619; -. DR DNASU; 5476; -. DR Ensembl; ENST00000191018; ENSP00000191018; ENSG00000064601. DR GeneID; 5476; -. DR KEGG; hsa:5476; -. DR UCSC; uc002xqh.3; human. DR CTD; 5476; -. DR GeneCards; GC20P044519; -. DR HGNC; HGNC:9251; CTSA. DR HPA; CAB024930; -. DR HPA; HPA031068; -. DR MIM; 256540; phenotype. DR MIM; 613111; gene. DR neXtProt; NX_P10619; -. DR Orphanet; 351; Galactosialidosis. DR PharmGKB; PA33572; -. DR eggNOG; COG2939; -. DR HOVERGEN; HBG053652; -. DR InParanoid; P10619; -. DR KO; K13289; -. DR OrthoDB; EOG4Z0B5K; -. DR PhylomeDB; P10619; -. DR Reactome; REACT_111217; Metabolism. DR Reactome; REACT_6900; Immune System. DR SignaLink; P10619; -. DR BindingDB; P10619; -. DR ChEMBL; CHEMBL6115; -. DR ChiTaRS; CTSA; human. DR EvolutionaryTrace; P10619; -. DR GeneWiki; Cathepsin_A; -. DR GenomeRNAi; 5476; -. DR NextBio; 21202; -. DR PRO; PR:P10619; -. DR ArrayExpress; P10619; -. DR Bgee; P10619; -. DR CleanEx; HS_CTSA; -. DR Genevestigator; P10619; -. DR GO; GO:0005783; C:endoplasmic reticulum; TAS:ProtInc. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; IDA:HPA. DR GO; GO:0004180; F:carboxypeptidase activity; TAS:ProtInc. DR GO; GO:0008047; F:enzyme activator activity; TAS:ProtInc. DR GO; GO:0004185; F:serine-type carboxypeptidase activity; IEA:InterPro. DR GO; GO:0006687; P:glycosphingolipid metabolic process; TAS:Reactome. DR GO; GO:0006886; P:intracellular protein transport; TAS:ProtInc. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome. DR InterPro; IPR001563; Peptidase_S10. DR InterPro; IPR018202; Peptidase_S10_AS. DR PANTHER; PTHR11802; PTHR11802; 1. DR Pfam; PF00450; Peptidase_S10; 1. DR PRINTS; PR00724; CRBOXYPTASEC. DR PROSITE; PS00560; CARBOXYPEPT_SER_HIS; 1. DR PROSITE; PS00131; CARBOXYPEPT_SER_SER; 1. PE 1: Evidence at protein level; KW 3D-structure; Carboxypeptidase; Complete proteome; KW Direct protein sequencing; Disease mutation; Disulfide bond; KW Glycoprotein; Hydrolase; Lysosome; Protease; Reference proteome; KW Signal; Zymogen. FT SIGNAL 1 28 FT CHAIN 29 480 Lysosomal protective protein. FT /FTId=PRO_0000004274. FT CHAIN 29 326 Lysosomal protective protein 32 kDa FT chain. FT /FTId=PRO_0000004275. FT CHAIN 327 480 Lysosomal protective protein 20 kDa FT chain. FT /FTId=PRO_0000004276. FT ACT_SITE 178 178 FT ACT_SITE 400 400 By similarity. FT ACT_SITE 457 457 FT CARBOHYD 145 145 N-linked (GlcNAc...). FT CARBOHYD 333 333 N-linked (GlcNAc...). FT DISULFID 88 362 FT DISULFID 240 256 FT DISULFID 241 246 FT DISULFID 281 331 FT VARIANT 49 49 Q -> R (in GSL). FT /FTId=VAR_001385. FT VARIANT 51 51 S -> Y (in GSL). FT /FTId=VAR_063018. FT VARIANT 65 65 W -> R (in GSL; dbSNP:rs28934603). FT /FTId=VAR_001386. FT VARIANT 90 90 S -> L (in GSL). FT /FTId=VAR_001387. FT VARIANT 132 132 V -> M (in GSL). FT /FTId=VAR_063019. FT VARIANT 236 236 L -> P (in GSL). FT /FTId=VAR_063020. FT VARIANT 249 249 Y -> N (in GSL; small amount of FT activity). FT /FTId=VAR_001388. FT VARIANT 395 395 Y -> C (in GSL; loss of activity). FT /FTId=VAR_001389. FT VARIANT 406 406 M -> T (in GSL). FT /FTId=VAR_063021. FT VARIANT 439 439 G -> S (in GSL). FT /FTId=VAR_063022. FT VARIANT 440 440 F -> V (in GSL). FT /FTId=VAR_001390. FT VARIANT 453 453 K -> E (in GSL). FT /FTId=VAR_063023. FT MUTAGEN 178 178 S->A: Inactivates the enzyme. FT MUTAGEN 457 457 H->Q: Inactivates the enzyme. FT CONFLICT 19 19 Missing (in Ref. 4; AAH00597). FT CONFLICT 56 56 G -> S (in Ref. 1; AAA36476). FT TURN 31 33 FT STRAND 49 55 FT STRAND 60 67 FT HELIX 73 75 FT STRAND 78 82 FT TURN 85 87 FT HELIX 91 95 FT TURN 96 98 FT STRAND 99 103 FT STRAND 110 112 FT HELIX 117 119 FT STRAND 120 126 FT STRAND 136 139 FT HELIX 146 163 FT HELIX 165 167 FT STRAND 172 177 FT HELIX 180 191 FT STRAND 199 206 FT HELIX 211 224 FT HELIX 230 240 FT HELIX 254 268 FT STRAND 269 271 FT STRAND 286 292 FT STRAND 295 298 FT HELIX 315 317 FT HELIX 318 321 FT STRAND 324 327 FT HELIX 335 341 FT HELIX 344 349 FT HELIX 364 369 FT STRAND 375 377 FT HELIX 378 387 FT STRAND 391 397 FT STRAND 401 403 FT HELIX 405 414 FT STRAND 419 429 FT STRAND 435 452 FT HELIX 459 462 FT HELIX 464 475 SQ SEQUENCE 480 AA; 54466 MW; 46B737DEE775C508 CRC64; MIRAAPPPLF LLLLLLLLLV SWASRGEAAP DQDEIQRLPG LAKQPSFRQY SGYLKGSGSK HLHYWFVESQ KDPENSPVVL WLNGGPGCSS LDGLLTEHGP FLVQPDGVTL EYNPYSWNLI ANVLYLESPA GVGFSYSDDK FYATNDTEVA QSNFEALQDF FRLFPEYKNN KLFLTGESYA GIYIPTLAVL VMQDPSMNLQ GLAVGNGLSS YEQNDNSLVY FAYYHGLLGN RLWSSLQTHC CSQNKCNFYD NKDLECVTNL QEVARIVGNS GLNIYNLYAP CAGGVPSHFR YEKDTVVVQD LGNIFTRLPL KRMWHQALLR SGDKVRMDPP CTNTTAASTY LNNPYVRKAL NIPEQLPQWD MCNFLVNLQY RRLYRSMNSQ YLKLLSSQKY QILLYNGDVD MACNFMGDEW FVDSLNQKME VQRRPWLVKY GDSGEQIAGF VKEFSHIAFL TIKGAGHMVP TDKPLAAFTM FSRFLNKQPY //