P10619 (PPGB_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Lysosomal protective protein
EC=3.4.16.5

Alternative name(s):
Carboxypeptidase C
Carboxypeptidase L
Cathepsin A
Protective protein cathepsin A
Short name=PPCA
Protective protein for beta-galactosidase

Cleaved into the following 2 chains:

1. Lysosomal protective protein 32 kDa chain
2. Lysosomal protective protein 20 kDa chain

Gene names

Name:	CTSA
Synonyms:	PPGB

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	480 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity. This protein is also a carboxypeptidase and can deamidate tachykinins. Ref.7
Catalytic activity	Release of a C-terminal amino acid with broad specificity.
Subunit structure	Heterodimer of a 32 kDa chain and a 20 kDa chain; disulfide-linked.
Subcellular location	Lysosome.
Involvement in disease	Galactosialidosis (GSL) [MIM:256540]: A lysosomal storage disease associated with a combined deficiency of beta-galactosidase and neuraminidase, secondary to a defect in cathepsin A. All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and a normal or mildly affected mental state. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12 Ref.13 Ref.14 Ref.15
Sequence similarities	Belongs to the peptidase S10 family.
Sequence caution	The sequence CAI20248.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Cellular component	Lysosome
Disease	Disease mutation
Domain	Signal
Molecular function	Carboxypeptidase Hydrolase Protease
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	glycosphingolipid metabolic process Traceable author statement. Source: Reactome intracellular protein transport Traceable author statement PubMed 1387645. Source: ProtInc phospholipid metabolic process Traceable author statement. Source: Reactome proteolysis Inferred from electronic annotation. Source: UniProtKB-KW small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	endoplasmic reticulum Traceable author statement PubMed 1387645. Source: ProtInc lysosomal lumen Traceable author statement. Source: Reactome mitochondrion Inferred from electronic annotation. Source: Compara nucleus Inferred from direct assay. Source: HPA
Molecular_function	carboxypeptidase activity Traceable author statement PubMed 2244901. Source: ProtInc enzyme activator activity Traceable author statement PubMed 3107551. Source: ProtInc serine-type carboxypeptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 28

28

Ref.5 Ref.6

Chain

29 – 480

452

Lysosomal protective protein

PRO_0000004274

Chain

29 – 326

298

Lysosomal protective protein 32 kDa chain

PRO_0000004275

Chain

327 – 480

154

Lysosomal protective protein 20 kDa chain

PRO_0000004276

Sites

Active site

178

1

Active site

400

1

By similarity

Active site

457

1

Amino acid modifications

Glycosylation

145

1

N-linked (GlcNAc...) Ref.8 Ref.9

Glycosylation

333

1

N-linked (GlcNAc...) Ref.9

Disulfide bond

88 ↔ 362

Disulfide bond

240 ↔ 256

Disulfide bond

241 ↔ 246

Disulfide bond

281 ↔ 331

Natural variations

Natural variant

49

1

Q → R in GSL. Ref.13

VAR_001385

Natural variant

51

1

S → Y in GSL. Ref.14

VAR_063018

Natural variant

65

1

W → R in GSL. Ref.13
Corresponds to variant rs28934603 [ dbSNP | Ensembl ].

VAR_001386

Natural variant

90

1

S → L in GSL. Ref.13

VAR_001387

Natural variant

132

1

V → M in GSL. Ref.14

VAR_063019

Natural variant

236

1

L → P in GSL. Ref.14

VAR_063020

Natural variant

249

1

Y → N in GSL; small amount of activity. Ref.13 Ref.14

VAR_001388

Natural variant

395

1

Y → C in GSL; loss of activity. Ref.13

VAR_001389

Natural variant

406

1

M → T in GSL. Ref.14

VAR_063021

Natural variant

439

1

G → S in GSL. Ref.14

VAR_063022

Natural variant

440

1

F → V in GSL. Ref.12 Ref.14

VAR_001390

Natural variant

453

1

K → E in GSL. Ref.15

VAR_063023

Experimental info

Mutagenesis

178

1

S → A: Inactivates the enzyme.

Mutagenesis

457

1

H → Q: Inactivates the enzyme.

Sequence conflict

19

1

Missing in AAH00597. Ref.4

Sequence conflict

56

1

G → S in AAA36476. Ref.1

Secondary structure

1

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480

Helix Strand Turn

Details...

Turn

31 – 33

3

Beta strand

49 – 55

7

Beta strand

60 – 67

8

Helix

73 – 75

3

Beta strand

78 – 82

5

Turn

85 – 87

3

Helix

91 – 95

5

Turn

96 – 98

3

Beta strand

99 – 103

5

Beta strand

110 – 112

3

Helix

117 – 119

3

Beta strand

120 – 126

7

Beta strand

136 – 139

4

Helix

146 – 163

18

Helix

165 – 167

3

Beta strand

172 – 177

6

Helix

180 – 191

12

Beta strand

199 – 206

8

Helix

211 – 224

14

Helix

230 – 240

11

Helix

254 – 268

15

Beta strand

269 – 271

3

Beta strand

286 – 292

7

Beta strand

295 – 298

4

Helix

315 – 317

3

Helix

318 – 321

4

Beta strand

324 – 327

4

Helix

335 – 341

7

Helix

344 – 349

6

Helix

364 – 369

6

Beta strand

375 – 377

3

Helix

378 – 387

10

Beta strand

391 – 397

7

Beta strand

401 – 403

3

Helix

405 – 414

10

Beta strand

419 – 429

11

Beta strand

435 – 452

18

Helix

459 – 462

4

Helix

464 – 475

12

Sequences

	Sequence		Length	Mass (Da)
	P10619 [UniParc]. Last modified April 16, 2002. Version 2. Checksum: 46B737DEE775C508	FASTA	480	54,466
	10 20 30 40 50 60 MIRAAPPPLF LLLLLLLLLV SWASRGEAAP DQDEIQRLPG LAKQPSFRQY SGYLKGSGSK 70 80 90 100 110 120 HLHYWFVESQ KDPENSPVVL WLNGGPGCSS LDGLLTEHGP FLVQPDGVTL EYNPYSWNLI 130 140 150 160 170 180 ANVLYLESPA GVGFSYSDDK FYATNDTEVA QSNFEALQDF FRLFPEYKNN KLFLTGESYA 190 200 210 220 230 240 GIYIPTLAVL VMQDPSMNLQ GLAVGNGLSS YEQNDNSLVY FAYYHGLLGN RLWSSLQTHC 250 260 270 280 290 300 CSQNKCNFYD NKDLECVTNL QEVARIVGNS GLNIYNLYAP CAGGVPSHFR YEKDTVVVQD 310 320 330 340 350 360 LGNIFTRLPL KRMWHQALLR SGDKVRMDPP CTNTTAASTY LNNPYVRKAL NIPEQLPQWD 370 380 390 400 410 420 MCNFLVNLQY RRLYRSMNSQ YLKLLSSQKY QILLYNGDVD MACNFMGDEW FVDSLNQKME 430 440 450 460 470 480 VQRRPWLVKY GDSGEQIAGF VKEFSHIAFL TIKGAGHMVP TDKPLAAFTM FSRFLNKQPY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Expression of cDNA encoding the human 'protective protein' associated with lysosomal beta-galactosidase and neuraminidase: homology to yeast proteases." Galjart N.J., Gillemans N., Harris A., van de Horst G.T.J., Verheijen F.W., Galjaard H., D'Azzo A. Cell 54:755-764(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[3]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta and Skin.
[5]	"A peptidase in human platelets that deamidates tachykinins. Probable identity with the lysosomal 'protective protein'." Jackman H.L., Tan F., Tamei H., Beurling-Harbury C., Li X.-Y., Skidgel R.A., Erdoes E.G. J. Biol. Chem. 265:11265-11272(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-53 AND 327-351. Tissue: Platelet.
[6]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-37. Tissue: Platelet.
[7]	"Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function." Galjart N.J., Morreau H., Willemsen R., Gillemans N., Bonten E.J., D'Azzo A. J. Biol. Chem. 266:14754-14762(1991) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS.
[8]	"Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach." Lewandrowski U., Moebius J., Walter U., Sickmann A. Mol. Cell. Proteomics 5:226-233(2006) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-145, MASS SPECTROMETRY. Tissue: Platelet.
[9]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-145 AND ASN-333, MASS SPECTROMETRY. Tissue: Liver.
[10]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism." Rudenko G., Bonten E., D'Azzo A., Hol W.G.J. Structure 3:1249-1259(1995) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
[12]	"A mutation in a mild form of galactosialidosis impairs dimerization of the protective protein and renders it unstable." Zhou X.Y., Galjart N.J., Willemsen R., Gillemans N., Galjaard H., D'Azzo A. EMBO J. 10:4041-4048(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GSL VAL-440.
[13]	"Protective protein gene mutations in galactosialidosis." Shimmoto M., Fukuhara Y., Itoh K., Oshima A., Sakuraba H., Suzuki Y. J. Clin. Invest. 91:2393-2398(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GSL ARG-49; ARG-65; LEU-90; ASN-249 AND CYS-395.
[14]	"Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis." Zhou X.Y., van der Spoel A., Rottier R., Hale G., Willemsen R., Berry G.T., Strisciuglio P., Morrone A., Zammarchi E., Andria G., d'Azzo A. Hum. Mol. Genet. 5:1977-1987(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GSL TYR-51; MET-132; PRO-236; ASN-249; THR-406; SER-439 AND VAL-440.
[15]	"Structural and functional study of K453E mutant protective protein/cathepsin A causing the late infantile form of galactosialidosis." Takiguchi K., Itoh K., Shimmoto M., Ozand P.T., Doi H., Sakuraba H. J. Hum. Genet. 45:200-206(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GSL GLU-453.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M22960 mRNA. Translation: AAA36476.1.
AK312898 mRNA. Translation: BAG35745.1.
AL008726 Genomic DNA. Translation: CAA15501.1.
AL008726 Genomic DNA. Translation: CAI20248.1. Different initiation.
BC000597 mRNA. Translation: AAH00597.1.
BC093009 mRNA. Translation: AAH93009.1.

IPI

IPI00021794.

PIR

A31589.

RefSeq

NP_000299.2. NM_000308.2.
NP_001121167.1. NM_001127695.1.
NP_001161066.1. NM_001167594.1.

UniGene

Hs.609336.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IVY	X-ray	2.20	A/B	29-480	[»]
3BP4	X-ray	1.85	C	2-10	[»]
3BP7	X-ray	1.80	C	2-10	[»]
3BXN	X-ray	1.86	C	2-10	[»]
4AZ0	X-ray	2.17	A	29-326	[»]
			B	327-480	[»]
4AZ3	X-ray	2.04	A	29-326	[»]
			B	327-480	[»]

ProteinModelPortal

P10619.

ModBase

Search...

Protein-protein interaction databases

IntAct

P10619. 8 interactions.

STRING

9606.ENSP00000361562.

Protein family/group databases

MEROPS

S10.002.

PTM databases

PhosphoSite

P10619.

Polymorphism databases

DMDM

20178316.

2D gel databases

OGP

P10619.

Proteomic databases

PaxDb

P10619.

PRIDE

P10619.

Protocols and materials databases

DNASU

5476.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000191018; ENSP00000191018; ENSG00000064601.
ENST00000372484; ENSP00000361562; ENSG00000064601.

GeneID

5476.

KEGG

hsa:5476.

UCSC

uc002xqh.3. human.

Organism-specific databases

CTD

5476.

GeneCards

GC20P044519.

HGNC

HGNC:9251. CTSA.

HPA

CAB024930.
HPA031068.

MIM

256540. phenotype.
613111. gene.

neXtProt

NX_P10619.

Orphanet

351. Galactosialidosis.

PharmGKB

PA33572.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG2939.

HOVERGEN

HBG053652.

InParanoid

P10619.

KO

K13289.

OrthoDB

EOG4Z0B5K.

PhylomeDB

P10619.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P10619.

Bgee

P10619.

CleanEx

HS_CTSA.

Genevestigator

P10619.

GermOnline

ENSG00000064601. Homo sapiens.

Family and domain databases

InterPro

IPR001563. Peptidase_S10.
IPR018202. Peptidase_S10_AS.
[Graphical view]

PANTHER

PTHR11802. PTHR11802. 1 hit.

Pfam

PF00450. Peptidase_S10. 1 hit.
[Graphical view]

PRINTS

PR00724. CRBOXYPTASEC.

PROSITE

PS00560. CARBOXYPEPT_SER_HIS. 1 hit.
PS00131. CARBOXYPEPT_SER_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P10619.

ChEMBL

CHEMBL6115.

ChiTaRS

CTSA. human.

EvolutionaryTrace

P10619.

GenomeRNAi

5476.

NextBio

21202.

SOURCE

Search...

Entry information

Entry name

PPGB_HUMAN

Accession

Primary (citable) accession number: P10619
Secondary accession number(s): B2R798 , Q561W6, Q5JZH1, Q96KJ2, Q9BR08, Q9BW68

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	April 16, 2002
Last modified:	May 1, 2013
This is version 166 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.