Granzyme A

Class of enzymes
Granzyme A
Identifiers
EC no.3.4.21.78
CAS no.143180-73-8
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins
GZMA
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

1OP8, 1ORF

Identifiers
AliasesGZMA, CTLA3, HFSP, granzyme A
External IDsOMIM: 140050; MGI: 109266; HomoloGene: 21237; GeneCards: GZMA; OMA:GZMA - orthologs
Gene location (Human)
Chromosome 5 (human)
Chr.Chromosome 5 (human)[1]
Chromosome 5 (human)
Genomic location for GZMA
Genomic location for GZMA
Band5q11.2Start55,102,646 bp[1]
End55,110,252 bp[1]
Gene location (Mouse)
Chromosome 13 (mouse)
Chr.Chromosome 13 (mouse)[2]
Chromosome 13 (mouse)
Genomic location for GZMA
Genomic location for GZMA
Band13 D2.2|13 63.93 cMStart113,230,359 bp[2]
End113,237,515 bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • granulocyte

  • blood

  • spleen

  • jejunal mucosa

  • lymph node

  • mucosa of transverse colon

  • duodenum

  • testicle

  • palpebral conjunctiva

  • rectum
Top expressed in
  • gastrula

  • jejunum

  • thymus

  • duodenum

  • blood

  • right lung lobe

  • spleen

  • ankle joint

  • decidua

  • mesenteric lymph nodes
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
  • peptidase activity
  • serine-type peptidase activity
  • serine-type endopeptidase activity
  • hydrolase activity
  • protein binding
  • protein homodimerization activity
Cellular component
  • immunological synapse
  • extracellular region
  • nucleus
Biological process
  • positive regulation of apoptotic process
  • negative regulation of DNA binding
  • proteolysis involved in cellular protein catabolic process
  • negative regulation of endodeoxyribonuclease activity
  • cytolysis
  • negative regulation of oxidoreductase activity
  • immune response
  • proteolysis
  • apoptotic process
  • response to bacterium
Sources:Amigo / QuickGO
Orthologs
SpeciesHumanMouse
Entrez

3001

14938

Ensembl

ENSG00000145649

ENSMUSG00000023132

UniProt

P12544

P11032

RefSeq (mRNA)

NM_006144

NM_010370

RefSeq (protein)

NP_006135

NP_034500

Location (UCSC)Chr 5: 55.1 – 55.11 MbChr 13: 113.23 – 113.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Granzyme A (GzmA, EC 3.4.21.78, CTLA3, HuTPS, T-cell associated protease 1, cytotoxic T lymphocyte serine protease, TSP-1, T-cell derived serine proteinase) is a tryptase[5][6][7] and is one of the five granzymes encoded in the human genome.[8][9][10] In humans, GzmA is encoded by the GZMA gene in proximity to the GZMK gene on chromosome 5. This enzyme is present in cytotoxic T lymphocyte (CTL) granules.

GzmA cleaves proteins after arginine or lysine basic residues. In CTL-targeted cells, it activates caspase-independent programmed cell death pathways that are unique and parallel to that of Granzyme B, although some substrates such as PARP-1[11] and lamin B[12] are shared with Granzyme B. Substrates of GzmA include Pro-IL-1β,[13] NDUFS3,[14] SET, APE1, and Ku70 among others. In vitro studies suggest that GzmA may have less cytotoxic capabilities than GzmB.[15][16]

In colorectal cancer, GzmA was associated with promotion of cancer development, which may be due to activation of inflammation-inducing cytokines from macrophages.[17]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000145649 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023132 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Simon MM, Hoschützky H, Fruth U, Simon HG, Kramer MD (December 1986). "Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes". The EMBO Journal. 5 (12): 3267–74. doi:10.1002/j.1460-2075.1986.tb04638.x. PMC 1167321. PMID 3545816.
  6. ^ Gershenfeld HK, Hershberger RJ, Shows TB, Weissman IL (February 1988). "Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease". Proceedings of the National Academy of Sciences of the United States of America. 85 (4): 1184–8. Bibcode:1988PNAS...85.1184G. doi:10.1073/pnas.85.4.1184. PMC 279731. PMID 3257574.
  7. ^ Odake S, Kam CM, Narasimhan L, Poe M, Blake JT, Krahenbuhl O, Tschopp J, Powers JC (February 1991). "Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins". Biochemistry. 30 (8): 2217–27. doi:10.1021/bi00222a027. PMID 1998680.
  8. ^ Hameed A, Lowrey DM, Lichtenheld M, Podack ER (Nov 1988). "Characterization of three serine esterases isolated from human IL-2 activated killer cells". J Immunol. 141 (9): 3142–7. doi:10.4049/jimmunol.141.9.3142. PMID 3262682.
  9. ^ Masson D, Zamai M, Tschopp J (Dec 1986). "Identification of granzyme A isolated from cytotoxic T-lymphocyte-granules as one of the proteases encoded by CTL-specific genes". FEBS Lett. 208 (1): 84–8. doi:10.1016/0014-5793(86)81537-X. PMID 3533635. S2CID 10670230.
  10. ^ "Entrez Gene: GZMA granzyme A (granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3)".
  11. ^ Zhu P, Martinvalet D, Chowdhury D, Zhang D, Schlesinger A, Lieberman J (2009-08-06). "The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1". Blood. 114 (6): 1205–1216. doi:10.1182/blood-2008-12-195768. ISSN 1528-0020. PMC 2723016. PMID 19506301.
  12. ^ Zhang D, Beresford PJ, Greenberg AH, Lieberman J (2001-05-08). "Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis". Proceedings of the National Academy of Sciences of the United States of America. 98 (10): 5746–5751. Bibcode:2001PNAS...98.5746Z. doi:10.1073/pnas.101329598. ISSN 0027-8424. PMC 33284. PMID 11331782.
  13. ^ Irmler M, Hertig S, MacDonald HR, Sadoul R, Becherer JD, Proudfoot A, Solari R, Tschopp J (1995-05-01). "Granzyme A is an interleukin 1 beta-converting enzyme". The Journal of Experimental Medicine. 181 (5): 1917–1922. doi:10.1084/jem.181.5.1917. ISSN 0022-1007. PMC 2191995. PMID 7722467.
  14. ^ Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J (2008-05-16). "Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death". Cell. 133 (4): 681–692. doi:10.1016/j.cell.2008.03.032. ISSN 1097-4172. PMC 2840390. PMID 18485875.
  15. ^ Martinvalet D, Walch M, Jensen D, Thiery J, Lieberman J (Oct 29, 2009). "Response: Granzyme A: cell death–inducing protease, proinflammatory agent, or both?". Blood. 114 (8): 3969–3970. doi:10.1182/blood-2009-08-233577. PMC 2773496.
  16. ^ Metkar SS, Menaa C, Pardo J, Wang B, Wallich R, Freudenberg M, Kim S, Raja SM, Shi L, Simon MM, Froelich CJ (2008-11-14). "Human and mouse granzyme A induce a proinflammatory cytokine response". Immunity. 29 (5): 720–733. doi:10.1016/j.immuni.2008.08.014. ISSN 1097-4180. PMID 18951048.
  17. ^ Santiago L, Castro M, Sanz-Pamplona R, Garzón M, Ramirez-Labrada A, Tapia E, Moreno V, Layunta E, Gil-Gómez G, Garrido M, Peña R, Lanuza PM, Comas L, Jaime-Sanchez P, Uranga-Murillo I (2020-07-07). "Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation". Cell Reports. 32 (1): 107847. doi:10.1016/j.celrep.2020.107847. hdl:10230/45276. ISSN 2211-1247. PMID 32640217.

Further reading

  • Pasternack MS, Bleier KJ, McInerney TN (1991). "Granzyme A binding to target cell proteins. Granzyme A binds to and cleaves nucleolin in vitro". J. Biol. Chem. 266 (22): 14703–8. doi:10.1016/S0021-9258(18)98743-0. PMID 1860869.
  • Poe M, Bennett CD, Biddison WE, et al. (1988). "Human cytotoxic lymphocyte tryptase. Its purification from granules and the characterization of inhibitor and substrate specificity". J. Biol. Chem. 263 (26): 13215–22. doi:10.1016/S0021-9258(18)37694-4. PMID 3047119.
  • Murphy ME, Moult J, Bleackley RC, et al. (1989). "Comparative molecular model building of two serine proteinases from cytotoxic T lymphocytes". Proteins. 4 (3): 190–204. doi:10.1002/prot.340040306. PMID 3237717. S2CID 35164948.
  • Gershenfeld HK, Hershberger RJ, Shows TB, Weissman IL (1988). "Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease". Proc. Natl. Acad. Sci. U.S.A. 85 (4): 1184–8. Bibcode:1988PNAS...85.1184G. doi:10.1073/pnas.85.4.1184. PMC 279731. PMID 3257574.
  • Krähenbühl O, Rey C, Jenne D, et al. (1988). "Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes". J. Immunol. 141 (10): 3471–7. doi:10.4049/jimmunol.141.10.3471. PMID 3263427.
  • Baetz K, Isaaz S, Griffiths GM (1995). "Loss of cytotoxic T lymphocyte function in Chediak-Higashi syndrome arises from a secretory defect that prevents lytic granule exocytosis". J. Immunol. 154 (11): 6122–31. doi:10.4049/jimmunol.154.11.6122. PMID 7751653.
  • Inoue M, Hoshino T, Fukuma T, et al. (1994). "Close co-localization of CD4 and a serine esterase tryptase TL2 on the cell-surface of human monocytoid and CD4+ lymphoid cells". Biochem. Biophys. Res. Commun. 201 (3): 1390–5. doi:10.1006/bbrc.1994.1857. PMID 7912927.
  • Fink TM, Lichter P, Wekerle H, et al. (1994). "The human granzyme A (HFSP, CTLA3) gene maps to 5q11-q12 and defines a new locus of the serine protease superfamily". Genomics. 18 (2): 401–3. doi:10.1006/geno.1993.1483. PMID 8288245.
  • Beresford PJ, Kam CM, Powers JC, Lieberman J (1997). "Recombinant human granzyme A binds to two putative HLA-associated proteins and cleaves one of them". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9285–90. Bibcode:1997PNAS...94.9285B. doi:10.1073/pnas.94.17.9285. PMC 23158. PMID 9256474.
  • Spaeny-Dekking EH, Hanna WL, Wolbink AM, et al. (1998). "Extracellular granzymes A and B in humans: detection of native species during CTL responses in vitro and in vivo". J. Immunol. 160 (7): 3610–6. doi:10.4049/jimmunol.160.7.3610. PMID 9531325.
  • Zhang D, Beresford PJ, Greenberg AH, Lieberman J (2001). "Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis". Proc. Natl. Acad. Sci. U.S.A. 98 (10): 5746–51. Bibcode:2001PNAS...98.5746Z. doi:10.1073/pnas.101329598. PMC 33284. PMID 11331782.
  • Beresford PJ, Zhang D, Oh DY, et al. (2001). "Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks". J. Biol. Chem. 276 (46): 43285–93. doi:10.1074/jbc.M108137200. PMID 11555662.
  • Fan Z, Beresford PJ, Zhang D, Lieberman J (2002). "HMG2 Interacts with the Nucleosome Assembly Protein SET and Is a Target of the Cytotoxic T-Lymphocyte Protease Granzyme A". Mol. Cell. Biol. 22 (8): 2810–20. doi:10.1128/MCB.22.8.2810-2820.2002. PMC 133744. PMID 11909973.
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  • Fan Z, Beresford PJ, Zhang D, et al. (2003). "Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A". Nat. Immunol. 4 (2): 145–53. doi:10.1038/ni885. PMID 12524539. S2CID 29433133.
  • Pinkoski MJ, Green DR (2003). "Granzyme A: the road less traveled". Nat. Immunol. 4 (2): 106–8. doi:10.1038/ni0203-106. PMID 12555094. S2CID 38687759.
  • Saito S, Iida A, Sekine A, et al. (2003). "Catalog of 680 variations among eight cytochrome p450 ( CYP) genes, nine esterase genes, and two other genes in the Japanese population". J. Hum. Genet. 48 (5): 249–70. doi:10.1007/s10038-003-0021-7. PMID 12721789.
  • Bell JK, Goetz DH, Mahrus S, et al. (2003). "The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity". Nat. Struct. Biol. 10 (7): 527–34. doi:10.1038/nsb944. PMID 12819769. S2CID 9608837.
  • v
  • t
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  • 1op8: Crystal Structure of Human Granzyme A
    1op8: Crystal Structure of Human Granzyme A
  • 1orf: The Oligomeric Structure of Human Granzyme A Reveals the Molecular Determinants of Substrate Specificity
    1orf: The Oligomeric Structure of Human Granzyme A Reveals the Molecular Determinants of Substrate Specificity
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