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P12544 (GRAA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 160. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length262 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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 processApoptosis
Cytolysis
   Cellular componentSecreted
   Coding sequence diversityAlternative promoter usage
Polymorphism
   DomainSignal
   Molecular functionHydrolase
Protease
Serine protease
   PTMDisulfide bond
Glycoprotein
Zymogen
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processapoptotic process

Traceable author statement Ref.10. 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

proteolysis involved in cellular protein catabolic process

Inferred from direct assay Ref.10. Source: UniProtKB

   Cellular_componentextracellular 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_functionprotein homodimerization activity

Inferred from direct assay Ref.14. Source: UniProtKB

serine-type endopeptidase activity

Inferred from direct assay PubMed 11331782Ref.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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2626In isoform alpha
Propeptide27 – 282Activation peptide (in isoform alpha)
PRO_0000027393
Chain29 – 262234Granzyme A
PRO_0000027394

Regions

Domain29 – 259231Peptidase S1

Sites

Active site691Charge relay system
Active site1141Charge relay system
Active site2121Charge relay system

Amino acid modifications

Glycosylation1701N-linked (GlcNAc...) Ref.11
Disulfide bond54 ↔ 70
Disulfide bond148 ↔ 218
Disulfide bond179 ↔ 197
Disulfide bond208 ↔ 234

Natural variations

Alternative sequence1 – 1717Missing in isoform beta.
VSP_038571
Alternative sequence18 – 236LLLIPE → MTKGLR in isoform beta.
VSP_038572
Natural variant1211M → T. Ref.1 Ref.2 Ref.4
Corresponds to variant rs3104233 [ dbSNP | Ensembl ].
VAR_024291

Experimental info

Sequence conflict33 – 342NE → DT no nucleotide entry Ref.5
Sequence conflict361T → V no nucleotide entry Ref.5
Sequence conflict471S → K no nucleotide entry Ref.5
Sequence conflict49 – 524DRKT → KPDS no nucleotide entry Ref.5
Sequence conflict621D → N no nucleotide entry Ref.5
Sequence conflict71 – 722NL → IP no nucleotide entry Ref.5

Secondary structure

........................................... 262
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform alpha [UniParc].

Last modified January 11, 2011. Version 2.
Checksum: FD773628BA6F301B

FASTA26228,999
        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 

« Hide

Isoform beta [UniParc].

Checksum: 7489DB5C158483F6
Show »

FASTA24527,109

References

« Hide '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. expand/collapse author list , 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.
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.
PIRA31372.
RefSeqNP_006135.1. NM_006144.3.
UniGeneHs.90708.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1HF1model-A29-262[»]
1OP8X-ray2.50A/B/C/D/E/F29-262[»]
1ORFX-ray2.40A29-262[»]
ProteinModelPortalP12544.
SMRP12544. Positions 29-260.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109256. 17 interactions.
IntActP12544. 4 interactions.
STRING9606.ENSP00000274306.

Chemistry

ChEMBLCHEMBL4307.

Protein family/group databases

MEROPSS01.135.

PTM databases

PhosphoSiteP12544.

Polymorphism databases

DMDM317373360.

Proteomic databases

PaxDbP12544.
PRIDEP12544.

Protocols and materials databases

DNASU3001.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000274306; ENSP00000274306; ENSG00000145649. [P12544-1]
GeneID3001.
KEGGhsa:3001.
UCSCuc003jpm.3. human. [P12544-1]

Organism-specific databases

CTD3001.
GeneCardsGC05P054398.
HGNCHGNC:4708. GZMA.
MIM140050. gene.
neXtProtNX_P12544.
PharmGKBPA29086.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5640.
HOGENOMHOG000251820.
HOVERGENHBG013304.
InParanoidP12544.
KOK01352.
OMAWIIMTIK.
OrthoDBEOG7W9RVH.
PhylomeDBP12544.
TreeFamTF333630.

Enzyme and pathway databases

BRENDA3.4.21.78. 2681.

Gene expression databases

BgeeP12544.
CleanExHS_GZMA.
GenevestigatorP12544.

Family and domain databases

InterProIPR001254. Peptidase_S1.
IPR018114. Peptidase_S1_AS.
IPR001314. Peptidase_S1A.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]
PfamPF00089. Trypsin. 1 hit.
[Graphical view]
PRINTSPR00722. CHYMOTRYPSIN.
SMARTSM00020. Tryp_SPc. 1 hit.
[Graphical view]
SUPFAMSSF50494. SSF50494. 1 hit.
PROSITEPS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP12544.
GeneWikiGZMA.
GenomeRNAi3001.
NextBio11900.
PROP12544.
SOURCESearch...

Entry information

Entry nameGRAA_HUMAN
AccessionPrimary (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 16, 2014
This is version 160 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM