GRAH_HUMAN
ID GRAH_HUMAN Reviewed; 246 AA.
AC P20718; G3V2C5; Q6XGZ0; Q6XGZ1;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 1.
DT 03-AUG-2022, entry version 187.
DE RecName: Full=Granzyme H;
DE EC=3.4.21.-;
DE AltName: Full=CCP-X;
DE AltName: Full=Cathepsin G-like 2;
DE Short=CTSGL2;
DE AltName: Full=Cytotoxic T-lymphocyte proteinase;
DE AltName: Full=Cytotoxic serine protease C;
DE Short=CSP-C;
DE Flags: Precursor;
GN Name=GZMH; Synonyms=CGL2, CTSGL2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2193684; DOI=10.1021/bi00469a003;
RA Meier M., Kwong P.C., Fregeau C.J., Atkinson E.A., Burrington M.,
RA Ehrman N., Sorensen O., Lin C.C., Wilkins J., Bleackley R.C.;
RT "Cloning of a gene that encodes a new member of the human cytotoxic cell
RT protease family.";
RL Biochemistry 29:4042-4049(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2049336; DOI=10.1093/intimm/3.1.57;
RA Haddad P., Jenne D.E., Tschopp J., Clement M.-V., Mathieu-Mahul D.,
RA Sasportes M.;
RT "Structure and evolutionary origin of the human granzyme H gene.";
RL Int. Immunol. 3:57-66(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2402757; DOI=10.1111/j.1399-0039.1990.tb01787.x;
RA Klein J.L., Selvakumar A., Trapani J.A., Dupont B.;
RT "Characterization of a novel, human cytotoxic lymphocyte-specific serine
RT protease cDNA clone (CSP-C).";
RL Tissue Antigens 35:220-228(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Leukemic T-cell;
RA Kothapalli R., Kusmartseva I., Loughran T.P. Jr.;
RT "Identification and characterization of granzyme H splice variants 2 and 3
RT from large granular lymphocyte leukemia.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 21-246 OF MUTANT ASN-102 ALONE AND
RP IN COMPLEX WITH SUBSTRATE PEPTIDE AND INHIBITOR, FUNCTION, SUBSTRATE
RP SPECIFICITY, AND DISULFIDE BONDS.
RX PubMed=22156497; DOI=10.4049/jimmunol.1101381;
RA Wang L., Zhang K., Wu L., Liu S., Zhang H., Zhou Q., Tong L., Sun F.,
RA Fan Z.;
RT "Structural insights into the substrate specificity of human granzyme H:
RT the functional roles of a novel RKR motif.";
RL J. Immunol. 188:765-773(2012).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 21-246 IN COMPLEX WITH SERPINB1,
RP FUNCTION, DISULFIDE BONDS, TISSUE SPECIFICITY, ACTIVITY REGULATION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=23269243; DOI=10.4049/jimmunol.1202542;
RA Wang L., Li Q., Wu L., Liu S., Zhang Y., Yang X., Zhu P., Zhang H.,
RA Zhang K., Lou J., Liu P., Tong L., Sun F., Fan Z.;
RT "Identification of SERPINB1 as a physiological inhibitor of human granzyme
RT H.";
RL J. Immunol. 190:1319-1330(2013).
CC -!- FUNCTION: Cytotoxic chymotrypsin-like serine protease with preference
CC for bulky and aromatic residues at the P1 position and acidic residues
CC at the P3' and P4' sites. Probably necessary for target cell lysis in
CC cell-mediated immune responses. Participates in the antiviral response
CC via direct cleavage of several proteins essential for viral
CC replication. {ECO:0000269|PubMed:22156497,
CC ECO:0000269|PubMed:23269243}.
CC -!- ACTIVITY REGULATION: Inhibited by SERPINB1.
CC {ECO:0000269|PubMed:23269243}.
CC -!- SUBCELLULAR LOCATION: Cytolytic granule {ECO:0000269|PubMed:23269243}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P20718-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P20718-2; Sequence=VSP_047073;
CC Name=3;
CC IsoId=P20718-3; Sequence=VSP_047573;
CC -!- TISSUE SPECIFICITY: Constitutively expressed in NK cells.
CC {ECO:0000269|PubMed:23269243}.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. Granzyme subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU00274}.
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DR EMBL; J02907; AAA76859.1; -; Genomic_DNA.
DR EMBL; M57888; AAA03514.1; -; Genomic_DNA.
DR EMBL; M36118; AAA03248.1; -; mRNA.
DR EMBL; M72150; AAA74885.1; -; Genomic_DNA.
DR EMBL; AY232657; AAP70247.1; -; mRNA.
DR EMBL; AY232658; AAP70248.1; -; mRNA.
DR EMBL; AL136018; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471078; EAW66004.1; -; Genomic_DNA.
DR EMBL; BC027974; AAH27974.1; -; mRNA.
DR CCDS; CCDS59243.1; -. [P20718-2]
DR CCDS; CCDS9632.1; -. [P20718-1]
DR PIR; A32692; A32692.
DR RefSeq; NP_001257710.1; NM_001270781.1. [P20718-2]
DR RefSeq; NP_219491.1; NM_033423.4. [P20718-1]
DR PDB; 3TJU; X-ray; 2.70 A; A=21-246.
DR PDB; 3TJV; X-ray; 2.40 A; A=21-246.
DR PDB; 3TK9; X-ray; 2.20 A; A=21-246.
DR PDB; 4GAW; X-ray; 3.00 A; A/B/C/D/E/F/G/H/I/J/K/L=21-246.
DR PDBsum; 3TJU; -.
DR PDBsum; 3TJV; -.
DR PDBsum; 3TK9; -.
DR PDBsum; 4GAW; -.
DR AlphaFoldDB; P20718; -.
DR SMR; P20718; -.
DR BioGRID; 109254; 99.
DR IntAct; P20718; 1.
DR MINT; P20718; -.
DR STRING; 9606.ENSP00000216338; -.
DR MEROPS; S01.147; -.
DR GlyConnect; 1291; 1 N-Linked glycan (1 site).
DR GlyGen; P20718; 3 sites, 1 N-linked glycan (1 site).
DR PhosphoSitePlus; P20718; -.
DR BioMuta; GZMH; -.
DR DMDM; 121590; -.
DR jPOST; P20718; -.
DR MassIVE; P20718; -.
DR PaxDb; P20718; -.
DR PeptideAtlas; P20718; -.
DR PRIDE; P20718; -.
DR ProteomicsDB; 32592; -.
DR ProteomicsDB; 53779; -. [P20718-1]
DR ProteomicsDB; 67801; -.
DR ProteomicsDB; 67802; -.
DR Antibodypedia; 9278; 218 antibodies from 33 providers.
DR DNASU; 2999; -.
DR Ensembl; ENST00000216338.9; ENSP00000216338.4; ENSG00000100450.13. [P20718-1]
DR Ensembl; ENST00000382548.4; ENSP00000371988.4; ENSG00000100450.13. [P20718-2]
DR GeneID; 2999; -.
DR KEGG; hsa:2999; -.
DR MANE-Select; ENST00000216338.9; ENSP00000216338.4; NM_033423.5; NP_219491.1.
DR UCSC; uc001wpr.3; human. [P20718-1]
DR CTD; 2999; -.
DR DisGeNET; 2999; -.
DR GeneCards; GZMH; -.
DR HGNC; HGNC:4710; GZMH.
DR HPA; ENSG00000100450; Tissue enhanced (bone marrow, lymphoid tissue).
DR MIM; 116831; gene.
DR neXtProt; NX_P20718; -.
DR OpenTargets; ENSG00000100450; -.
DR PharmGKB; PA29088; -.
DR VEuPathDB; HostDB:ENSG00000100450; -.
DR eggNOG; KOG3627; Eukaryota.
DR GeneTree; ENSGT01030000234551; -.
DR HOGENOM; CLU_006842_1_0_1; -.
DR InParanoid; P20718; -.
DR OMA; IKATEIC; -.
DR OrthoDB; 1076876at2759; -.
DR PhylomeDB; P20718; -.
DR TreeFam; TF333630; -.
DR BRENDA; 3.4.21.B59; 2681.
DR PathwayCommons; P20718; -.
DR Reactome; R-HSA-2022377; Metabolism of Angiotensinogen to Angiotensins.
DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR SignaLink; P20718; -.
DR BioGRID-ORCS; 2999; 24 hits in 1068 CRISPR screens.
DR GeneWiki; GZMH; -.
DR GenomeRNAi; 2999; -.
DR Pharos; P20718; Tbio.
DR PRO; PR:P20718; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; P20718; protein.
DR Bgee; ENSG00000100450; Expressed in granulocyte and 110 other tissues.
DR ExpressionAtlas; P20718; baseline and differential.
DR Genevisible; P20718; HS.
DR GO; GO:0044194; C:cytolytic granule; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; NAS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; NAS:UniProtKB.
DR GO; GO:0019835; P:cytolysis; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd00190; Tryp_SPc; 1.
DR Gene3D; 2.40.10.10; -; 2.
DR InterPro; IPR009003; Peptidase_S1_PA.
DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR001254; Trypsin_dom.
DR InterPro; IPR018114; TRYPSIN_HIS.
DR InterPro; IPR033116; TRYPSIN_SER.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytolysis; Disulfide bond;
KW Glycoprotein; Hydrolase; Lysosome; Protease; Reference proteome;
KW Serine protease; Signal; Zymogen.
FT SIGNAL 1..18
FT PROPEP 19..20
FT /note="Activation peptide"
FT /id="PRO_0000027413"
FT CHAIN 21..246
FT /note="Granzyme H"
FT /id="PRO_0000027414"
FT DOMAIN 21..244
FT /note="Peptidase S1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT REGION 46..48
FT /note="Mediates the preference for acidic residues at the
FT P3' and P4' sites"
FT ACT_SITE 64
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT ACT_SITE 108
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT ACT_SITE 202
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 104
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 179
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 49..65
FT DISULFID 142..208
FT DISULFID 172..187
FT VAR_SEQ 69..199
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_047573"
FT VAR_SEQ 114..199
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_047073"
FT VARIANT 84
FT /note="R -> Q (in dbSNP:rs20545)"
FT /id="VAR_014556"
FT CONFLICT 68
FT /note="S -> R (in Ref. 4; AAP70248)"
FT /evidence="ECO:0000305"
FT STRAND 35..44
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 46..55
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 58..61
FT /evidence="ECO:0007829|PDB:3TK9"
FT HELIX 63..65
FT /evidence="ECO:0007829|PDB:3TJV"
FT STRAND 68..75
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 87..96
FT /evidence="ECO:0007829|PDB:3TK9"
FT HELIX 98..100
FT /evidence="ECO:0007829|PDB:4GAW"
FT TURN 102..105
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 110..116
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 121..123
FT /evidence="ECO:0007829|PDB:4GAW"
FT STRAND 141..147
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 149..153
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 160..167
FT /evidence="ECO:0007829|PDB:3TK9"
FT HELIX 169..175
FT /evidence="ECO:0007829|PDB:3TK9"
FT TURN 176..178
FT /evidence="ECO:0007829|PDB:3TK9"
FT TURN 182..184
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 185..189
FT /evidence="ECO:0007829|PDB:3TK9"
FT TURN 199..203
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 205..208
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 211..218
FT /evidence="ECO:0007829|PDB:3TK9"
FT STRAND 221..223
FT /evidence="ECO:0007829|PDB:4GAW"
FT STRAND 227..231
FT /evidence="ECO:0007829|PDB:3TK9"
FT TURN 232..235
FT /evidence="ECO:0007829|PDB:3TK9"
FT HELIX 236..244
FT /evidence="ECO:0007829|PDB:3TK9"
SQ SEQUENCE 246 AA; 27315 MW; CA6A87F3DA5F1E71 CRC64;
MQPFLLLLAF LLTPGAGTEE IIGGHEAKPH SRPYMAFVQF LQEKSRKRCG GILVRKDFVL
TAAHCQGSSI NVTLGAHNIK EQERTQQFIP VKRPIPHPAY NPKNFSNDIM LLQLERKAKW
TTAVRPLRLP SSKAQVKPGQ LCSVAGWGYV SMSTLATTLQ EVLLTVQKDC QCERLFHGNY
SRATEICVGD PKKTQTGFKG DSGGPLVCKD VAQGILSYGN KKGTPPGVYI KVSHFLPWIK
RTMKRL
