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   27-MAR-2024, entry version 178.
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; 8.
DR   IntAct; P51124; 1.
DR   STRING; 9606.ENSP00000264553; -.
DR   ChEMBL; CHEMBL4523234; -.
DR   MEROPS; S01.139; -.
DR   CarbonylDB; P51124; -.
DR   GlyCosmos; P51124; 1 site, No reported glycans.
DR   GlyGen; P51124; 2 sites.
DR   iPTMnet; P51124; -.
DR   PhosphoSitePlus; P51124; -.
DR   BioMuta; GZMM; -.
DR   DMDM; 296434527; -.
DR   MassIVE; P51124; -.
DR   PaxDb; 9606-ENSP00000264553; -.
DR   PeptideAtlas; P51124; -.
DR   ProteomicsDB; 56282; -.
DR   Antibodypedia; 22316; 192 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   AGR; HGNC:4712; -.
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; 5318576at2759; -.
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; 19 hits in 1148 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 cell types or tissues.
DR   ExpressionAtlas; P51124; baseline and differential.
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; IMP:UniProtKB.
DR   GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR   GO; GO:0031640; P:killing of cells of another organism; 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; Trypsin-like serine proteases; 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   PANTHER; PTHR24271:SF51; GRANZYME M; 1.
DR   PANTHER; PTHR24271; KALLIKREIN-RELATED; 1.
DR   Pfam; PF00089; Trypsin; 1.
DR   PRINTS; PR00722; CHYMOTRYPSIN.
DR   SMART; SM00020; Tryp_SPc; 1.
DR   SUPFAM; SSF50494; Trypsin-like serine proteases; 1.
DR   PROSITE; PS50240; TRYPSIN_DOM; 1.
DR   PROSITE; PS00134; TRYPSIN_HIS; 1.
DR   PROSITE; PS00135; TRYPSIN_SER; 1.
DR   Genevisible; P51124; HS.
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
//