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Protein

Granzyme A

Gene

GZMA

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Abundant protease in the cytosolic granules of cytotoxic T-cells and NK-cells which activates caspase-independent cell death with morphological features of apoptosis when delivered into the target cell through the immunological synapse. It cleaves after Lys or Arg. Cleaves APEX1 after 'Lys-31' and destroys its oxidative repair activity. Cleaves the nucleosome assembly protein SET after 'Lys-189', which disrupts its nucleosome assembly activity and allows the SET complex to translocate into the nucleus to nick and degrade the DNA.4 Publications

Catalytic activityi

Hydrolysis of proteins, including fibronectin, type IV collagen and nucleolin. Preferential cleavage: -Arg-|-Xaa-, -Lys-|-Xaa- >> -Phe-|-Xaa- in small molecule substrates.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei69Charge relay system1
Active sitei114Charge relay system1
Active sitei212Charge relay system1

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB
  • serine-type endopeptidase activity Source: UniProtKB

GO - Biological processi

  • apoptotic process Source: UniProtKB
  • cytolysis Source: UniProtKB-KW
  • immune response Source: UniProtKB
  • negative regulation of DNA binding Source: UniProtKB
  • negative regulation of endodeoxyribonuclease activity Source: UniProtKB
  • negative regulation of oxidoreductase activity Source: UniProtKB
  • positive regulation of apoptotic process Source: UniProtKB
  • proteolysis involved in cellular protein catabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Serine protease

Keywords - Biological processi

Apoptosis, Cytolysis

Enzyme and pathway databases

BioCyciZFISH:HS07268-MONOMER.
BRENDAi3.4.21.78. 2681.
SIGNORiP12544.

Protein family/group databases

MEROPSiS01.135.

Names & Taxonomyi

Protein namesi
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 namesi
Name:GZMA
Synonyms:CTLA3, HFSP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

HGNCiHGNC:4708. GZMA.

Subcellular locationi

GO - Cellular componenti

  • extracellular region Source: UniProtKB-SubCell
  • immunological synapse Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Organism-specific databases

DisGeNETi3001.
OpenTargetsiENSG00000145649.
PharmGKBiPA29086.

Chemistry databases

ChEMBLiCHEMBL4307.

Polymorphism and mutation databases

BioMutaiGZMA.
DMDMi317373360.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 26In isoform alphaAdd BLAST26
PropeptideiPRO_000002739327 – 28Activation peptide (in isoform alpha)3 Publications2
ChainiPRO_000002739429 – 262Granzyme AAdd BLAST234

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi54 ↔ 70
Disulfide bondi148 ↔ 218
Glycosylationi170N-linked (GlcNAc...)1 Publication1
Disulfide bondi179 ↔ 197
Disulfide bondi208 ↔ 234

Keywords - PTMi

Disulfide bond, Glycoprotein, Zymogen

Proteomic databases

MaxQBiP12544.
PaxDbiP12544.
PeptideAtlasiP12544.
PRIDEiP12544.

PTM databases

iPTMnetiP12544.
PhosphoSitePlusiP12544.

Expressioni

Inductioni

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.1 Publication

Gene expression databases

BgeeiENSG00000145649.
CleanExiHS_GZMA.
GenevisibleiP12544. HS.

Organism-specific databases

HPAiHPA054134.

Interactioni

Subunit structurei

Homodimer; disulfide-linked. Interacts with APEX1.3 Publications

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi109256. 17 interactors.
IntActiP12544. 4 interactors.
STRINGi9606.ENSP00000274306.

Structurei

Secondary structure

1262
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi43 – 47Combined sources5
Beta strandi49 – 51Combined sources3
Beta strandi53 – 60Combined sources8
Beta strandi63 – 66Combined sources4
Beta strandi77 – 81Combined sources5
Beta strandi83 – 87Combined sources5
Beta strandi93 – 95Combined sources3
Beta strandi97 – 102Combined sources6
Turni108 – 110Combined sources3
Beta strandi116 – 122Combined sources7
Beta strandi127 – 130Combined sources4
Beta strandi147 – 154Combined sources8
Beta strandi156 – 160Combined sources5
Beta strandi167 – 174Combined sources8
Helixi176 – 179Combined sources4
Turni182 – 189Combined sources8
Beta strandi195 – 199Combined sources5
Beta strandi215 – 218Combined sources4
Beta strandi221 – 228Combined sources8
Beta strandi241 – 245Combined sources5
Helixi248 – 258Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1HF1model-A29-262[»]
1OP8X-ray2.50A/B/C/D/E/F29-262[»]
1ORFX-ray2.40A29-262[»]
ProteinModelPortaliP12544.
SMRiP12544.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP12544.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini29 – 259Peptidase S1PROSITE-ProRule annotationAdd BLAST231

Sequence similaritiesi

Belongs to the peptidase S1 family. Granzyme subfamily.PROSITE-ProRule annotation
Contains 1 peptidase S1 domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG3627. Eukaryota.
COG5640. LUCA.
GeneTreeiENSGT00760000118895.
HOGENOMiHOG000251820.
HOVERGENiHBG013304.
InParanoidiP12544.
KOiK01352.
OMAiDRKVCND.
OrthoDBiEOG091G0AH5.
PhylomeDBiP12544.
TreeFamiTF333630.

Family and domain databases

CDDicd00190. Tryp_SPc. 1 hit.
InterProiIPR009003. Peptidase_S1_PA.
IPR001314. Peptidase_S1A.
IPR001254. Trypsin_dom.
IPR018114. TRYPSIN_HIS.
IPR033116. TRYPSIN_SER.
[Graphical view]
PfamiPF00089. Trypsin. 1 hit.
[Graphical view]
PRINTSiPR00722. CHYMOTRYPSIN.
SMARTiSM00020. Tryp_SPc. 1 hit.
[Graphical view]
SUPFAMiSSF50494. SSF50494. 1 hit.
PROSITEiPS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative promoter usage. AlignAdd to basket

Isoform alpha (identifier: P12544-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MRNSYRFLAS SLSVVVSLLL IPEDVCEKII GGNEVTPHSR PYMVLLSLDR
60 70 80 90 100
KTICAGALIA KDWVLTAAHC NLNKRSQVIL GAHSITREEP TKQIMLVKKE
110 120 130 140 150
FPYPCYDPAT REGDLKLLQL MEKAKINKYV TILHLPKKGD DVKPGTMCQV
160 170 180 190 200
AGWGRTHNSA SWSDTLREVN ITIIDRKVCN DRNHYNFNPV IGMNMVCAGS
210 220 230 240 250
LRGGRDSCNG DSGSPLLCEG VFRGVTSFGL ENKCGDPRGP GVYILLSKKH
260
LNWIIMTIKG AV
Length:262
Mass (Da):28,999
Last modified:January 11, 2011 - v2
Checksum:iFD773628BA6F301B
GO
Isoform beta (identifier: P12544-2) [UniParc]FASTAAdd to basket

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

Show »
Length:245
Mass (Da):27,109
Checksum:i7489DB5C158483F6
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti33 – 34NE → DT no nucleotide entry (PubMed:17180578).Curated2
Sequence conflicti36T → V no nucleotide entry (PubMed:17180578).Curated1
Sequence conflicti47S → K no nucleotide entry (PubMed:17180578).Curated1
Sequence conflicti49 – 52DRKT → KPDS no nucleotide entry (PubMed:17180578).Curated4
Sequence conflicti62D → N no nucleotide entry (PubMed:17180578).Curated1
Sequence conflicti71 – 72NL → IP no nucleotide entry (PubMed:17180578).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_024291121M → T.3 PublicationsCorresponds to variant rs3104233dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0385711 – 17Missing in isoform beta. 1 PublicationAdd BLAST17
Alternative sequenceiVSP_03857218 – 23LLLIPE → MTKGLR in isoform beta. 1 Publication6

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS3965.1. [P12544-1]
PIRiA31372.
RefSeqiNP_006135.1. NM_006144.3.
UniGeneiHs.90708.

Genome annotation databases

EnsembliENST00000274306; ENSP00000274306; ENSG00000145649. [P12544-1]
GeneIDi3001.
KEGGihsa:3001.
UCSCiuc003jpm.4. human. [P12544-1]

Keywords - Coding sequence diversityi

Alternative promoter usage, Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS3965.1. [P12544-1]
PIRiA31372.
RefSeqiNP_006135.1. NM_006144.3.
UniGeneiHs.90708.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1HF1model-A29-262[»]
1OP8X-ray2.50A/B/C/D/E/F29-262[»]
1ORFX-ray2.40A29-262[»]
ProteinModelPortaliP12544.
SMRiP12544.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109256. 17 interactors.
IntActiP12544. 4 interactors.
STRINGi9606.ENSP00000274306.

Chemistry databases

ChEMBLiCHEMBL4307.

Protein family/group databases

MEROPSiS01.135.

PTM databases

iPTMnetiP12544.
PhosphoSitePlusiP12544.

Polymorphism and mutation databases

BioMutaiGZMA.
DMDMi317373360.

Proteomic databases

MaxQBiP12544.
PaxDbiP12544.
PeptideAtlasiP12544.
PRIDEiP12544.

Protocols and materials databases

DNASUi3001.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000274306; ENSP00000274306; ENSG00000145649. [P12544-1]
GeneIDi3001.
KEGGihsa:3001.
UCSCiuc003jpm.4. human. [P12544-1]

Organism-specific databases

CTDi3001.
DisGeNETi3001.
GeneCardsiGZMA.
HGNCiHGNC:4708. GZMA.
HPAiHPA054134.
MIMi140050. gene.
neXtProtiNX_P12544.
OpenTargetsiENSG00000145649.
PharmGKBiPA29086.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3627. Eukaryota.
COG5640. LUCA.
GeneTreeiENSGT00760000118895.
HOGENOMiHOG000251820.
HOVERGENiHBG013304.
InParanoidiP12544.
KOiK01352.
OMAiDRKVCND.
OrthoDBiEOG091G0AH5.
PhylomeDBiP12544.
TreeFamiTF333630.

Enzyme and pathway databases

BioCyciZFISH:HS07268-MONOMER.
BRENDAi3.4.21.78. 2681.
SIGNORiP12544.

Miscellaneous databases

EvolutionaryTraceiP12544.
GeneWikiiGZMA.
GenomeRNAii3001.
PROiP12544.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000145649.
CleanExiHS_GZMA.
GenevisibleiP12544. HS.

Family and domain databases

CDDicd00190. Tryp_SPc. 1 hit.
InterProiIPR009003. Peptidase_S1_PA.
IPR001314. Peptidase_S1A.
IPR001254. Trypsin_dom.
IPR018114. TRYPSIN_HIS.
IPR033116. TRYPSIN_SER.
[Graphical view]
PfamiPF00089. Trypsin. 1 hit.
[Graphical view]
PRINTSiPR00722. CHYMOTRYPSIN.
SMARTiSM00020. Tryp_SPc. 1 hit.
[Graphical view]
SUPFAMiSSF50494. SSF50494. 1 hit.
PROSITEiPS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGRAA_HUMAN
AccessioniPrimary (citable) accession number: P12544
Secondary accession number(s): A4PHN1, Q6IB36
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: January 11, 2011
Last modified: November 2, 2016
This is version 182 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Caution

Exons 1a and 1b of the sequence reported in PubMed:17180578 are of human origin, however exon 2 shows strong similarity to the rat sequence.Curated

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Peptidase families
    Classification of peptidase families and list of entries
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.