P12544 (GRAA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Granzyme A
EC=3.4.21.78

Alternative name(s):
CTL tryptase
Cytotoxic T-lymphocyte proteinase 1
Fragmentin-1
Granzyme-1
Hanukkah factor
Short name=H factor
Short name=HF

Gene names

Name:	GZMA
Synonyms:	CTLA3, HFSP

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	262 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	This enzyme is necessary for target cell lysis in cell-mediated immune responses. It cleaves after Lys or Arg. Cleaves APEX1 after 'Lys-31' and destroys its oxidative repair activity. Involved in apoptosis. Ref.10
Catalytic activity	Hydrolysis of proteins, including fibronectin, type IV collagen and nucleolin. Preferential cleavage: -Arg-|-Xaa-, -Lys-|-Xaa- >> -Phe-|-Xaa- in small molecule substrates.
Subunit structure	Homodimer; disulfide-linked. Interacts with APEX1. Ref.10
Subcellular location	Isoform alpha: Secreted. Cytoplasmic granule.
Induction	Dexamethasone (DEX) induces expression of isoform beta and represses expression of isoform alpha. The alteration in expression is mediated by binding of glucocorticoid receptor to independent promoters adjacent to the alternative first exons of isoform alpha and isoform beta. Ref.5
Sequence similarities	Belongs to the peptidase S1 family. Granzyme subfamily. Contains 1 peptidase S1 domain.
Caution	Exons 1a and 1b of the sequence reported in Ref.5 are of human origin, however exon 2 shows strong similarity to the rat sequence.

Ontologies

Keywords
Biological process	Apoptosis Cytolysis
Cellular component	Secreted
Coding sequence diversity	Alternative promoter usage Polymorphism
Domain	Signal
Molecular function	Hydrolase Protease Serine protease
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cleavage of lamin involved in execution phase of apoptosis Inferred from direct assay PubMed 11331782. Source: UniProtKB cytolysis Inferred from electronic annotation. Source: UniProtKB-KW immune response Traceable author statement Ref.10. Source: UniProtKB negative regulation of DNA binding Inferred from direct assay Ref.10. Source: UniProtKB negative regulation of endodeoxyribonuclease activity Inferred from direct assay Ref.10. Source: UniProtKB negative regulation of oxidoreductase activity Inferred from direct assay Ref.10. Source: UniProtKB positive regulation of apoptotic process Inferred from direct assay Ref.10. Source: UniProtKB
Cellular_component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell immunological synapse Traceable author statement Ref.10. Source: UniProtKB nucleus Traceable author statement PubMed 11909973. Source: UniProtKB
Molecular_function	protein homodimerization activity Inferred from direct assay Ref.14. Source: UniProtKB serine-type endopeptidase activity Inferred from direct assay Ref.14. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative promoter usage. [Align] [Select]

Isoform alpha (identifier: P12544-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform beta (identifier: P12544-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-17: Missing.
     18-23: LLLIPE → MTKGLR

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 26

26

In isoform alpha

Propeptide

27 – 28

2

Activation peptide (in isoform alpha)

PRO_0000027393

Chain

29 – 262

234

Granzyme A

PRO_0000027394

Regions

Domain

29 – 259

231

Peptidase S1

Sites

Active site

69

1

Charge relay system

Active site

114

1

Charge relay system

Active site

212

1

Charge relay system

Amino acid modifications

Glycosylation

170

1

N-linked (GlcNAc...) Ref.11

Disulfide bond

54 ↔ 70

Disulfide bond

148 ↔ 218

Disulfide bond

179 ↔ 197

Disulfide bond

208 ↔ 234

Natural variations

Alternative sequence

1 – 17

17

Missing in isoform beta.

VSP_038571

Alternative sequence

18 – 23

6

LLLIPE → MTKGLR in isoform beta.

VSP_038572

Natural variant

121

1

M → T. Ref.1 Ref.2 Ref.4
Corresponds to variant rs3104233 [ dbSNP | Ensembl ].

VAR_024291

Experimental info

Sequence conflict

33 – 34

2

NE → DT no nucleotide entry Ref.5

Sequence conflict

36

1

T → V no nucleotide entry Ref.5

Sequence conflict

47

1

S → K no nucleotide entry Ref.5

Sequence conflict

49 – 52

4

DRKT → KPDS no nucleotide entry Ref.5

Sequence conflict

62

1

D → N no nucleotide entry Ref.5

Sequence conflict

71 – 72

2

NL → IP no nucleotide entry Ref.5

Secondary structure

1

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262

Helix Strand Turn

Details...

Beta strand

43 – 47

5

Beta strand

49 – 51

3

Beta strand

53 – 60

8

Beta strand

63 – 66

4

Beta strand

77 – 81

5

Beta strand

83 – 87

5

Beta strand

93 – 95

3

Beta strand

97 – 102

6

Turn

108 – 110

3

Beta strand

116 – 122

7

Beta strand

127 – 130

4

Beta strand

147 – 154

8

Beta strand

156 – 160

5

Beta strand

167 – 174

8

Helix

176 – 179

4

Turn

182 – 189

8

Beta strand

195 – 199

5

Beta strand

215 – 218

4

Beta strand

221 – 228

8

Beta strand

241 – 245

5

Helix

248 – 258

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform alpha [UniParc]. Last modified January 11, 2011. Version 2. Checksum: FD773628BA6F301B	FASTA	262	28,999
	10 20 30 40 50 60 MRNSYRFLAS SLSVVVSLLL IPEDVCEKII GGNEVTPHSR PYMVLLSLDR KTICAGALIA 70 80 90 100 110 120 KDWVLTAAHC NLNKRSQVIL GAHSITREEP TKQIMLVKKE FPYPCYDPAT REGDLKLLQL 130 140 150 160 170 180 MEKAKINKYV TILHLPKKGD DVKPGTMCQV AGWGRTHNSA SWSDTLREVN ITIIDRKVCN 190 200 210 220 230 240 DRNHYNFNPV IGMNMVCAGS LRGGRDSCNG DSGSPLLCEG VFRGVTSFGL ENKCGDPRGP 250 260 GVYILLSKKH LNWIIMTIKG AV
	Isoform beta [UniParc]. Checksum: 7489DB5C158483F6	FASTA	245	27,109
	10 20 30 40 50 60 MTKGLRDVCE KIIGGNEVTP HSRPYMVLLS LDRKTICAGA LIAKDWVLTA AHCNLNKRSQ 70 80 90 100 110 120 VILGAHSITR EEPTKQIMLV KKEFPYPCYD PATREGDLKL LQLMEKAKIN KYVTILHLPK 130 140 150 160 170 180 KGDDVKPGTM CQVAGWGRTH NSASWSDTLR EVNITIIDRK VCNDRNHYNF NPVIGMNMVC 190 200 210 220 230 240 AGSLRGGRDS CNGDSGSPLL CEGVFRGVTS FGLENKCGDP RGPGVYILLS KKHLNWIIMT IKGAV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease." Gershenfeld H.K., Hershberger R.J., Shows T.B., Weissman I.L. Proc. Natl. Acad. Sci. U.S.A. 85:1184-1188(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA), VARIANT THR-121. Tissue: T-cell.
[2]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA), VARIANT THR-121.
[3]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M. Nature 431:268-274(2004) [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] (ISOFORM ALPHA), VARIANT THR-121. Tissue: Blood.
[5]	"Glucocorticoid-induced alternative promoter usage for a novel 5' variant of granzyme A." Ruike Y., Katsuma S., Hirasawa A., Tsujimoto G. J. Hum. Genet. 52:172-178(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, NUCLEOTIDE SEQUENCE [MRNA] OF 1-34 (ISOFORM BETA), ALTERNATIVE PROMOTER USAGE, INDUCTION.
[6]	"The upstream region of the human granzyme A locus contains both positive and negative transcriptional regulatory elements." Goralski T.J., Krensky A.M. Submitted (NOV-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-23.
[7]	"Human cytotoxic lymphocyte tryptase. Its purification from granules and the characterization of inhibitor and substrate specificity." Poe M., Bennett C.D., Biddison W.E., Blake J.T., Norton G.P., Rodkey J.A., Sigal N.H., Turner R.V., Wu J.K., Zweerink H.J. J. Biol. Chem. 263:13215-13222(1988) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-53.
[8]	"Characterization of three serine esterases isolated from human IL-2 activated killer cells." Hameed A., Lowrey D.M., Lichtenheld M., Podack E.R. J. Immunol. 141:3142-3147(1988) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-40, CHARACTERIZATION.
[9]	"Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes." Kraehenbuhl O., Rey C., Jenne D.E., Lanzavecchia A., Groscurth P., Carrel S., Tschopp J. J. Immunol. 141:3471-3477(1988) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-39, CHARACTERIZATION.
[10]	"Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A." Fan Z., Beresford P.J., Zhang D., Xu Z., Novina C.D., Yoshida A., Pommier Y., Lieberman J. Nat. Immunol. 4:145-153(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH APEX1.
[11]	"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-170, MASS SPECTROMETRY. Tissue: Liver.
[12]	"Comparative molecular model building of two serine proteinases from cytotoxic T lymphocytes." Murphy M.E.P., Moult J., Bleackley R.C., Gershenfeld H., Weissman I.L., James M.N.G. Proteins 4:190-204(1988) [PubMed] [Europe PMC] [Abstract] Cited for: 3D-STRUCTURE MODELING OF 29-262.
[13]	"The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity." Bell J.K., Goetz D.H., Mahrus S., Harris J.L., Fletterick R.J., Craik C.S. Nat. Struct. Biol. 10:527-534(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 29-262 IN COMPLEX WITH A TRIPEPTIDE CMK INHIBITOR.
[14]	"Crystal structure of the apoptosis-inducing human granzyme A dimer." Hink-Schauer C., Estebanez-Perpina E., Kurschus F.C., Bode W., Jenne D.E. Nat. Struct. Biol. 10:535-540(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 29-262 IN COMPLEX WITH SUBSTRATE.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M18737 mRNA. Translation: AAA52647.1.
CR456968 mRNA. Translation: CAG33249.1.
AC091977 Genomic DNA. No translation available.
BC015739 mRNA. Translation: AAH15739.1.
AB284134 mRNA. Translation: BAF56159.1.
U40006 Genomic DNA. Translation: AAD00009.1.

IPI

IPI00024657.
IPI00954888.

PIR

A31372.

RefSeq

NP_006135.1. NM_006144.3.

UniGene

Hs.90708.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HF1	model	-	A	29-262	[»]
1OP8	X-ray	2.50	A/B/C/D/E/F	29-262	[»]
1ORF	X-ray	2.40	A	29-262	[»]

ProteinModelPortal

P12544.

SMR

P12544. Positions 29-260.

ModBase

Search...

Protein-protein interaction databases

IntAct

P12544. 4 interactions.

STRING

9606.ENSP00000274306.

Protein family/group databases

MEROPS

S01.135.

PTM databases

PhosphoSite

P12544.

Polymorphism databases

DMDM

121581.

Proteomic databases

PaxDb

P12544.

PRIDE

P12544.

Protocols and materials databases

DNASU

3001.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000274306; ENSP00000274306; ENSG00000145649.

GeneID

3001.

KEGG

hsa:3001.

UCSC

uc003jpm.3. human.

Organism-specific databases

CTD

3001.

GeneCards

GC05P054398.

HGNC

HGNC:4708. GZMA.

MIM

140050. gene.

neXtProt

NX_P12544.

PharmGKB

PA29086.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5640.

HOGENOM

HOG000251820.

HOVERGEN

HBG013304.

InParanoid

P12544.

KO

K01352.

OMA

PVIGMNM.

OrthoDB

EOG4SXNDS.

Enzyme and pathway databases

BRENDA

3.4.21.78. 2681.

Pathway_Interaction_DB

il12_2pathway. IL12-mediated signaling events.

Gene expression databases

Bgee

P12544.

CleanEx

HS_GZMA.

Genevestigator

P12544.

GermOnline

ENSG00000145649. Homo sapiens.

Family and domain databases

InterPro

IPR001254. Peptidase_S1.
IPR018114. Peptidase_S1_AS.
IPR001314. Peptidase_S1A.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]

Pfam

PF00089. Trypsin. 1 hit.
[Graphical view]

PRINTS

PR00722. CHYMOTRYPSIN.

SMART

SM00020. Tryp_SPc. 1 hit.
[Graphical view]

SUPFAM

SSF50494. Pept_Ser_Cys. 1 hit.

PROSITE

PS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL4307.

EvolutionaryTrace

P12544.

GenomeRNAi

3001.

NextBio

11900.

SOURCE

Search...

Entry information

Entry name

GRAA_HUMAN

Accession

Primary (citable) accession number: P12544
Secondary accession number(s): A4PHN1, Q6IB36

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	January 11, 2011
Last modified:	April 3, 2013
This is version 150 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.