GRAM_HUMAN
ID GRAM_HUMAN Reviewed; 257 AA.
AC P51124;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Granzyme M;
DE EC=3.4.21.-;
DE AltName: Full=Met-1 serine protease;
DE Short=Hu-Met-1;
DE AltName: Full=Met-ase;
DE AltName: Full=Natural killer cell granular protease;
DE Flags: Precursor;
GN Name=GZMM; Synonyms=MET1;
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 [MRNA], AND VARIANT GLY-221.
RX PubMed=8245461;
RA Smyth M.J., Sayers T.J., Wiltrout T., Powers J.C., Trapani J.A.;
RT "Met-ase: cloning and distinct chromosomal location of a serine protease
RT preferentially expressed in human natural killer cells.";
RL J. Immunol. 151:6195-6205(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLY-221.
RX PubMed=7713495; DOI=10.1006/geno.1994.1651;
RA Pilat D., Fink T.M., Obermaier-Skrobanek B., Zimmer M., Wekerle H.,
RA Lichter P., Jenne D.E.;
RT "The human Met-ase gene (GZMM): structure, sequence, and close physical
RT linkage to the serine protease gene cluster on 19p13.3.";
RL Genomics 24:445-450(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-221.
RC TISSUE=Pancreas, and Spleen;
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 [5]
RP FUNCTION, TISSUE SPECIFICITY, AND SUBSTRATES.
RX PubMed=18523284; DOI=10.4049/jimmunol.180.12.8184;
RA Bovenschen N., de Koning P.J., Quadir R., Broekhuizen R., Damen J.M.,
RA Froelich C.J., Slijper M., Kummer J.A.;
RT "NK cell protease granzyme M targets alpha-tubulin and disorganizes the
RT microtubule network.";
RL J. Immunol. 180:8184-8191(2008).
RN [6]
RP FUNCTION.
RX PubMed=20406824; DOI=10.1074/jbc.m109.083170;
RA Hu D., Liu S., Shi L., Li C., Wu L., Fan Z.;
RT "Cleavage of survivin by Granzyme M triggers degradation of the survivin-X-
RT linked inhibitor of apoptosis protein (XIAP) complex to free caspase
RT activity leading to cytolysis of target tumor cells.";
RL J. Biol. Chem. 285:18326-18335(2010).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 26-257, ACTIVE SITE, AND
RP DISULFIDE BONDS.
RX PubMed=19542453; DOI=10.4049/jimmunol.0803088;
RA Wu L., Wang L., Hua G., Liu K., Yang X., Zhai Y., Bartlam M., Sun F.,
RA Fan Z.;
RT "Structural basis for proteolytic specificity of the human apoptosis-
RT inducing granzyme M.";
RL J. Immunol. 183:421-429(2009).
CC -!- FUNCTION: Cleaves peptide substrates after methionine, leucine, and
CC norleucine. Physiological substrates include EZR, alpha-tubulins and
CC the apoptosis inhibitor BIRC5/Survivin. Promotes caspase activation and
CC subsequent apoptosis of target cells. {ECO:0000269|PubMed:18523284,
CC ECO:0000269|PubMed:20406824}.
CC -!- INTERACTION:
CC P51124; Q6NX45: ZNF774; NbExp=3; IntAct=EBI-12119998, EBI-10251462;
CC -!- SUBCELLULAR LOCATION: Secreted. Cytoplasmic granule. Note=Granules of
CC large granular lymphocytes.
CC -!- TISSUE SPECIFICITY: Highly and constitutively expressed in activated
CC natural killer (NK) cells. {ECO:0000269|PubMed:18523284}.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. Granzyme subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU00274}.
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DR EMBL; L23134; AAA59582.1; -; mRNA.
DR EMBL; L36922; AAA57262.1; -; Genomic_DNA.
DR EMBL; L36936; AAA57257.1; -; Genomic_DNA.
DR EMBL; AC011556; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC025701; AAH25701.1; -; mRNA.
DR CCDS; CCDS12031.1; -.
DR PIR; A55634; A55634.
DR RefSeq; NP_001245280.1; NM_001258351.1.
DR RefSeq; NP_005308.1; NM_005317.3.
DR PDB; 2ZGC; X-ray; 1.96 A; A=26-257.
DR PDB; 2ZGH; X-ray; 2.17 A; A=26-257.
DR PDB; 2ZGJ; X-ray; 2.30 A; A=26-257.
DR PDB; 2ZKS; X-ray; 2.70 A; A=26-257.
DR PDBsum; 2ZGC; -.
DR PDBsum; 2ZGH; -.
DR PDBsum; 2ZGJ; -.
DR PDBsum; 2ZKS; -.
DR AlphaFoldDB; P51124; -.
DR SMR; P51124; -.
DR BioGRID; 109259; 6.
DR IntAct; P51124; 1.
DR STRING; 9606.ENSP00000264553; -.
DR ChEMBL; CHEMBL4523234; -.
DR MEROPS; S01.139; -.
DR CarbonylDB; P51124; -.
DR GlyGen; P51124; 1 site.
DR iPTMnet; P51124; -.
DR PhosphoSitePlus; P51124; -.
DR BioMuta; GZMM; -.
DR DMDM; 296434527; -.
DR MassIVE; P51124; -.
DR PaxDb; P51124; -.
DR PeptideAtlas; P51124; -.
DR PRIDE; P51124; -.
DR ProteomicsDB; 56282; -.
DR Antibodypedia; 22316; 174 antibodies from 32 providers.
DR DNASU; 3004; -.
DR Ensembl; ENST00000264553.6; ENSP00000264553.1; ENSG00000197540.8.
DR GeneID; 3004; -.
DR KEGG; hsa:3004; -.
DR MANE-Select; ENST00000264553.6; ENSP00000264553.1; NM_005317.4; NP_005308.2.
DR UCSC; uc002low.3; human.
DR CTD; 3004; -.
DR DisGeNET; 3004; -.
DR GeneCards; GZMM; -.
DR HGNC; HGNC:4712; GZMM.
DR HPA; ENSG00000197540; Tissue enhanced (bone marrow, lymphoid tissue).
DR MIM; 600311; gene.
DR neXtProt; NX_P51124; -.
DR OpenTargets; ENSG00000197540; -.
DR PharmGKB; PA29090; -.
DR VEuPathDB; HostDB:ENSG00000197540; -.
DR eggNOG; KOG3627; Eukaryota.
DR GeneTree; ENSGT00940000162161; -.
DR HOGENOM; CLU_006842_1_0_1; -.
DR InParanoid; P51124; -.
DR OMA; DPFKPPV; -.
DR OrthoDB; 1314811at2759; -.
DR PhylomeDB; P51124; -.
DR TreeFam; TF335738; -.
DR BRENDA; 3.4.21.78; 2681.
DR BRENDA; 3.4.21.B2; 2681.
DR PathwayCommons; P51124; -.
DR Reactome; R-HSA-173736; Alternative complement activation.
DR SignaLink; P51124; -.
DR BioGRID-ORCS; 3004; 7 hits in 1070 CRISPR screens.
DR EvolutionaryTrace; P51124; -.
DR GeneWiki; GZMM; -.
DR GenomeRNAi; 3004; -.
DR Pharos; P51124; Tbio.
DR PRO; PR:P51124; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; P51124; protein.
DR Bgee; ENSG00000197540; Expressed in granulocyte and 103 other tissues.
DR ExpressionAtlas; P51124; baseline and differential.
DR Genevisible; P51124; HS.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IMP:UniProtKB.
DR GO; GO:0008236; F:serine-type peptidase activity; TAS:ProtInc.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0008219; P:cell death; IMP:UniProtKB.
DR GO; GO:0019835; P:cytolysis; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0001913; P:T cell mediated cytotoxicity; IEA:Ensembl.
DR CDD; cd00190; Tryp_SPc; 1.
DR Gene3D; 2.40.10.10; -; 2.
DR InterPro; IPR033040; GZMM.
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 PANTHER; PTHR24271:SF51; PTHR24271:SF51; 1.
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; Apoptosis; Cytolysis; Disulfide bond; Glycoprotein;
KW Hydrolase; Immunity; Innate immunity; Protease; Reference proteome;
KW Secreted; Serine protease; Signal; Zymogen.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT PROPEP 24..25
FT /note="Activation peptide"
FT /evidence="ECO:0000255"
FT /id="PRO_0000027421"
FT CHAIN 26..257
FT /note="Granzyme M"
FT /id="PRO_0000027422"
FT DOMAIN 26..254
FT /note="Peptidase S1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT ACT_SITE 66
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:19542453"
FT ACT_SITE 111
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:19542453"
FT ACT_SITE 207
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:19542453"
FT CARBOHYD 177
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 51..67
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274,
FT ECO:0000269|PubMed:19542453"
FT DISULFID 145..213
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274,
FT ECO:0000269|PubMed:19542453"
FT DISULFID 176..192
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274,
FT ECO:0000269|PubMed:19542453"
FT DISULFID 203..230
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274,
FT ECO:0000269|PubMed:19542453"
FT VARIANT 221
FT /note="R -> G (in dbSNP:rs1599882)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:7713495, ECO:0000269|PubMed:8245461"
FT /id="VAR_051829"
FT STRAND 40..45
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 48..57
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 60..63
FT /evidence="ECO:0007829|PDB:2ZGC"
FT HELIX 65..68
FT /evidence="ECO:0007829|PDB:2ZGC"
FT HELIX 72..74
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 75..80
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 82..86
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 89..98
FT /evidence="ECO:0007829|PDB:2ZGC"
FT TURN 105..107
FT /evidence="ECO:0007829|PDB:2ZGJ"
FT STRAND 113..119
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 144..149
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 164..170
FT /evidence="ECO:0007829|PDB:2ZGC"
FT HELIX 173..176
FT /evidence="ECO:0007829|PDB:2ZGC"
FT TURN 179..184
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 190..194
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 210..213
FT /evidence="ECO:0007829|PDB:2ZGC"
FT TURN 214..217
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 218..223
FT /evidence="ECO:0007829|PDB:2ZGC"
FT STRAND 238..242
FT /evidence="ECO:0007829|PDB:2ZGC"
FT HELIX 243..245
FT /evidence="ECO:0007829|PDB:2ZGC"
FT HELIX 246..253
FT /evidence="ECO:0007829|PDB:2ZGC"
SQ SEQUENCE 257 AA; 27545 MW; B4E815CE455F7371 CRC64;
MEACVSSLLV LALGALSVGS SFGTQIIGGR EVIPHSRPYM ASLQRNGSHL CGGVLVHPKW
VLTAAHCLAQ RMAQLRLVLG LHTLDSPGLT FHIKAAIQHP RYKPVPALEN DLALLQLDGK
VKPSRTIRPL ALPSKRQVVA AGTRCSMAGW GLTHQGGRLS RVLRELDLQV LDTRMCNNSR
FWNGSLSPSM VCLAADSKDQ APCKGDSGGP LVCGKGRVLA RVLSFSSRVC TDIFKPPVAT
AVAPYVSWIR KVTGRSA
