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Information on EC 3.4.21.B2 - granzyme M and Organism(s) Homo sapiens and UniProt Accession P51124
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3.4.21.B2 granzyme MSpecify your search results
Word Map
- 3.4.21.B2
- lymphocyte
- granule
-
killer
- perforin
- medicine
-
cell-mediated
-
virus-infected
-
cytolysis
-
pore-forming
-
caspase-independent
-
thiobenzyl
- serpins
-
perforin-dependent
-
m-mediated
- norleucine
-
noncytotoxic
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
endopeptidase activity. Cleaves substrates containing a methionine side chain at P1
Synonyms
granzyme m, met-ase-1, gzm m, hgzmm, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CAS REGISTRY NUMBER
COMMENTARY
159745-66-1
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ezrin + H2O
?
granzyme M directly and efficiently cleaves the actin-plasma membrane linker ezrin
-
-
?
heterogeneous nuclear ribonucleoprotein K + H2O
?
-
granzyme M most efficiently cleaves heterogeneous nuclear ribonucleoprotein K in the presence of RNA at multiple sites, thereby likely destroying heterogeneous nuclear ribonucleoprotein K function
-
?
human Fas-associated protein with Death Domain + H2O
?
-
cleavage at residue Met196
-
?
mouse Fas-associated protein with Death Domain mutant V193M/L194S + H2O
?
no substrate: wild-type mouse Fas-associated protein with Death Domain lacking a residue corresponding to Met196 of the human substrate
cleavage at residue M193
-
?
N-benzyloxycarbonyl-alanyl-alanyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-alanyl-alanyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-alanyl-aspartyl-methionine-thiobenzylester + H2O
-benzyloxycarbonyl-alanyl-aspartyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-alanyl-lysyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-alanyl-lysyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-alanyl-prolyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-alanyl-prolyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-alanyl-seryl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-alanyl-seryl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-aspartyl-prolyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-aspartyl-prolyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-lysyl-prolyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-lysyl-prolyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-prolyl-prolyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-prolyl-prolyl-methionine + phenylmethanethiol
-
-
-
?
N-benzyloxycarbonyl-seryl-prolyl-methionine-thiobenzylester + H2O
N-benzyloxycarbonyl-seryl-prolyl-methionine + phenylmethanethiol
-
-
-
?
N2-Cbz-L-Asp(O-tBut)-L-Pro-L-Met thiobenzyl ester + H2O
N2-Cbz-L-Asp(O-tBut)-L-Pro-L-Met + phenylmethanethiol
-
-
-
?
N2-CBZ-O3-tBut-L-Ser-L-Pro-L-Met-SBzl + H2O
N2-CBZ-O3-tBut-L-Ser-L-Pro-L-Met + phenylmethanethiol
-
-
-
?
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionyl thiobenzyl ester + H2O
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionine + phenylmethanethiol
-
-
-
?
survivin + H2O
?
the inhibitor of the apoptosis gene family member survivin is a physiological substrate for GzmM. GzmM hydrolyzes survivin at Leu-138 to remove the last four C-terminal residues. The truncated form is more rapidly hydrolyzed through proteasome-mediated degradation
-
-
?
topoisomerase II alpha + H2O
?
-
cleavage of topoisomerase II alpha by granzyme M at Leu1280 separates topoisomerase II alpha functional domains from the nuclear localization signals and leads to nuclear exit of topoisomerase II alpha catalytic activity
-
?
acetyl-GRLL-7-amido-4-methylcoumarin + H2O
acetyl-GRLL + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KEPL-7-amido-4-methylcoumarin + H2O
acetyl-KEPL + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KEPM-7-amido-4-methylcoumarin + H2O
acetyl-KEPM + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KVAM-7-amido-4-methylcoumarin + H2O
acetyl-KVAM + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KVPL-7-amido-4-methylcoumarin + H2O
acetyl-KVPL + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KVPM-7-amido-4-methylcoumarin + H2O
acetyl-KVPM + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KYAL-7-amido-4-methylcoumarin + H2O
acetyl-KYAL + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KYPL-7-amido-4-methylcoumarin + H2O
acetyl-KYPL + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-KYPM-7-amido-4-methylcoumarin + H2O
acetyl-KYPM + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-MEPL-7-amido-4-methylcoumarin + H2O
acetyl-MEPL + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-RYPL-7-amido-4-methylcoumarin + H2O
acetyl-RYPL + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-VPL-7-amido-4-methylcoumarin + H2O
acetyl-VPL + 7-amino-4-methylcoumarin
-
-
-
-
?
N-tert-butoxycarbonyl-Ala-Ala-Met thiobenzyl ester + H2O
N-tert-butoxycarbonyl-Ala-Ala-Met + phenylmethanethiol
-
activity only occurs with deletion mutants, but not with wild-type enzyme
-
?
N-tert-butoxycarbonyl-Ala-Ala-Met-thiobenzyl ester + H2O
N-tert-butoxycarbonyl-Ala-Ala-Met + phenylmethanethiol
-
cleaves thiobenzylester substrates specifically after methionine, norleucine or leucine residues in the primary substrate site P1
-
?
proteinase inhibitor 9 + H2O
?
-
effective hydrolysis and inactivation, bypassing proteinase inhibitor 9 inhibition of granzyme B
-
-
?
alpha-tubulin + H2O
?
direct alpha-tubulin proteolysis by granzyme M is complex and occurs at multiple cleavage sites, one of them being Leu at position 269. Granzyme M disturbs tubulin polymerization dynamics in vitro and induces microtubule network disorganization in tumor cells in vivo
-
-
?
alpha-tubulin + H2O
?
direct alpha-tubulin proteolysis by granzyme M is complex and occurs at multiple cleavage sites, one of them being Leu at position 269. Granzyme M disturbed tubulin polymerization dynamics in vitro and induced microtubule network disorganization in tumor cells in vivo
-
-
?
nucleophosmin + H2O
?
the nucleolar phosphoprotein, nucleophosmin (NPM), is cleaved and inactivated. Targeting of NPM by granzyme M may contribute to tumor cell eradication by abolishing NPM function
-
-
?
nucleophosmin + H2O
?
the nucleolar phosphoprotein, nucleophosmin (NPM), is cleaved and inactivated
-
-
?
inhibitor of caspase-activated DNase + H2O
?
-
direct degradation to release the nuclease activity of caspase-activated DNase for damaging DNA
-
-
?
poly(ADP-ribose) polymerase + H2O
?
-
cleavage to prevent cellular DNA repair and force apoptosis
-
-
?
additional information
?
-
the enzyme has a strong preference for Pro at the P2 position and Ala, Ser, or Asp at the P3 position
-
-
?
additional information
?
-
-
the enzyme has a strong preference for Pro at the P2 position and Ala, Ser, or Asp at the P3 position
-
-
?
additional information
?
-
isolated granzyme M induces cell death and disorganizes the microtubule network by targeting alpha-tubulin. Granzyme M inactivates the GzmB inhibitor protease inhibitor 9, thereby increasing the susceptibility of target cells to granzyme B-induced apoptosis
-
-
?
additional information
?
-
the recombinant GrM protein displays proteolytic activity only against a synthetic substrate that matches with the known cleavage specificity of the granzyme, which is after a Leu
-
-
?
additional information
?
-
-
the recombinant GrM protein displays proteolytic activity only against a synthetic substrate that matches with the known cleavage specificity of the granzyme, which is after a Leu
-
-
?
additional information
?
-
-
cleaves the carboxyl side of long narrow hydrophobic amino acids, such as methionine, but not large, bulky hydrophobic amino acids such as phenylalanine
-
?
additional information
?
-
-
hydrolyzes substrates containing a methionine-side chain at P1
-
?
additional information
?
-
-
participates in target cell death inflicted by cytotoxic lymphocytes
-
?
additional information
?
-
-
involved in granule exocytosis form of target cell death induced by cytotoxic lymphocytes
-
?
additional information
?
-
-
preference of proline over alanine at P2 and leucine over norleucine over methionine at P1, broad specificity at P3 and P4
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
alpha-tubulin + H2O
?
direct alpha-tubulin proteolysis by granzyme M is complex and occurs at multiple cleavage sites, one of them being Leu at position 269. Granzyme M disturbs tubulin polymerization dynamics in vitro and induces microtubule network disorganization in tumor cells in vivo
-
-
?
ezrin + H2O
?
granzyme M directly and efficiently cleaves the actin-plasma membrane linker ezrin
-
-
?
heterogeneous nuclear ribonucleoprotein K + H2O
?
-
granzyme M most efficiently cleaves heterogeneous nuclear ribonucleoprotein K in the presence of RNA at multiple sites, thereby likely destroying heterogeneous nuclear ribonucleoprotein K function
-
?
nucleophosmin + H2O
?
the nucleolar phosphoprotein, nucleophosmin (NPM), is cleaved and inactivated. Targeting of NPM by granzyme M may contribute to tumor cell eradication by abolishing NPM function
-
-
?
additional information
?
-
isolated granzyme M induces cell death and disorganizes the microtubule network by targeting alpha-tubulin. Granzyme M inactivates the GzmB inhibitor protease inhibitor 9, thereby increasing the susceptibility of target cells to granzyme B-induced apoptosis
-
-
?
additional information
?
-
-
participates in target cell death inflicted by cytotoxic lymphocytes
-
?
additional information
?
-
-
involved in granule exocytosis form of target cell death induced by cytotoxic lymphocytes
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
in Gzm M there are cationic sites, cs1 and cs2, that may participate in binding of Gzm M to the cell surface, thereby promoting its uptake and eventual release into the cytoplasm
additional information
-
in Gzm M there are cationic sites, cs1 and cs2, that may participate in binding of Gzm M to the cell surface, thereby promoting its uptake and eventual release into the cytoplasm
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
a series of peptide phosphonates and chloromethyl ketones tested, neither inhibitor type proved to be especially potent toward the enzyme, including the general serine protease inhibitor, 3,4-dichloroisocoumarin
-
additional information
-
a series of peptide phosphonates and chloromethyl ketones tested, neither inhibitor type proved to be especially potent toward the enzyme, including the general serine protease inhibitor, 3,4-dichloroisocoumarin
-
additional information
inhibitors bound to the granzyme active site show that the dimer also contributes to substrate specificity in a unique manner by extending the active-site cleft
-
additional information
-
inhibitors bound to the granzyme active site show that the dimer also contributes to substrate specificity in a unique manner by extending the active-site cleft
-
additional information
noncleavable L138A survivin overexpression can significantly inhibit GzmM-mediated X-linked inhibitor of apoptosis protein degradation, caspase activation, and GzmM- and natural killer cell-induced cytotoxicity
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
survivin silencing promotes X-linked inhibitor of apoptosis protein degradation and enhances GzmM-induced caspase activation as well as GzmM- and natural killer cell-induced cytolysis of target tumor cells
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0263 - 0.083
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionyl thiobenzyl ester
0.079
N-benzyloxycarbonyl-alanyl-alanyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.184
N-benzyloxycarbonyl-alanyl-alanyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
0.188
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine-thiobenzylester
-
0.236
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
1.02
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
0.267
N-benzyloxycarbonyl-alanyl-aspartyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.793
N-benzyloxycarbonyl-alanyl-lysyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
0.22
N-benzyloxycarbonyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.694
N-benzyloxycarbonyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
0.21
N-benzyloxycarbonyl-alanyl-seryl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
2.66
N-benzyloxycarbonyl-alanyl-seryl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
0.441
N-benzyloxycarbonyl-aspartyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.361
N-benzyloxycarbonyl-lysyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.036
N-benzyloxycarbonyl-phenylalanyl-prolyl-methionine-thiobenzylester
-
0.181
N-benzyloxycarbonyl-phenylalanyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.217
N-benzyloxycarbonyl-prolyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.92
N-benzyloxycarbonyl-seryl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.129
N2-Cbz-L-Asp(O-tBut)-L-Pro-L-Met thiobenzyl ester
murine granzyme M with bovine serum albumin
0.0366
N2-CBZ-O3-tBut-L-Ser-L-Pro-L-Met-SBzl
murine granzyme M with bovine serum albumin
0.0263
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionyl thiobenzyl ester
-
0.083
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionyl thiobenzyl ester
murine granzyme M with bovine serum albumin
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.03 - 0.335
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionyl thiobenzyl ester
2.46
N-benzyloxycarbonyl-alanyl-alanyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
4.35
N-benzyloxycarbonyl-alanyl-alanyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
13.1
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine-thiobenzylester
-
16.1
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
30
N-benzyloxycarbonyl-alanyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
0.438
N-benzyloxycarbonyl-alanyl-aspartyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
6.07
N-benzyloxycarbonyl-alanyl-lysyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
12.3
N-benzyloxycarbonyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
18.1
N-benzyloxycarbonyl-alanyl-prolyl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
3.56
N-benzyloxycarbonyl-alanyl-seryl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
12.8
N-benzyloxycarbonyl-alanyl-seryl-methionine-thiobenzylester
murine granzyme M without bovine serum albumin
29
N-benzyloxycarbonyl-aspartyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.031 - 0.51
N-benzyloxycarbonyl-lysyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
8.01
N-benzyloxycarbonyl-lysyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.0784
N-benzyloxycarbonyl-phenylalanyl-prolyl-methionine-thiobenzylester
-
0.634
N-benzyloxycarbonyl-phenylalanyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
6.08
N-benzyloxycarbonyl-phenylalanyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.973
N-benzyloxycarbonyl-prolyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
6.08
N-benzyloxycarbonyl-prolyl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
0.26
N-benzyloxycarbonyl-seryl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
52.1
N-benzyloxycarbonyl-seryl-prolyl-methionine-thiobenzylester
murine granzyme M with bovine serum albumin
2.13
N2-Cbz-L-Asp(O-tBut)-L-Pro-L-Met thiobenzyl ester
murine granzyme M with bovine serum albumin
0.161
N2-CBZ-O3-tBut-L-Ser-L-Pro-L-Met-SBzl
murine granzyme M with bovine serum albumin
0.03
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionyl thiobenzyl ester
-
0.335
N2-[(benzyloxy)carbonyl]-N6-(tert-butoxycarbonyl)-L-lysyl-L-prolyl-L-methionyl thiobenzyl ester
murine granzyme M with bovine serum albumin
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
granzyme M is transiently elevated in the circulation following lipopolysaccharide administration in humans
additional information
CD4+ T cell, CD8+ T cell, natural killer T cell and gammadelta T cell
granzyme M is expressed by human cytomegalovirus-specific CD8+ T cells both in latently infected healthy individuals and in transplant patients during primary human cytomegalovirus infection
additional information
expressed in almost all NK, NKT and gammadelta T-cells and 35% of all Tc cells
additional information
present in KHYG-1 cells, absent from Jurkat T-cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
in absence of granzyme M colonic inflammation is enhanced. The absence of granzyme expression also has effects on gut permeability, tissue cytokine/chemokine dynamics, and neutrophil infiltration during disease
physiological function
physiological function
Gzm M shows apoptotic activity both by caspase dependent and independent pathways
physiological function
GzmM associates with survivin. Survivin cleavage by GzmM abolishes the stability of the survivin-X-linked inhibitor of apoptosis protein complex and enhances X-linked inhibitor of apoptosis protein hydrolysis, which amplifies caspase-9 and 3 activation of target tumor cells
physiological function
granzyme M induced cell death is largely caspase-dependent with various hallmarks of classical apoptosis, coinciding with caspase-independent G2/M cell cycle arrest. The nuclear enzyme topoisomerase II alpha is a physiological substrate of granzyme M. Cleavage of topoisomerase II alpha by granzyme M at Leu1280 separates topoisomerase II alpha functional domains from the nuclear localization signals, leading to nuclear exit of topoisomerase II alpha catalytic activity, thereby rendering it nonfunctional. Similar to the apoptotic phenotype of granzyme M, topoisomerase II alpha depletion in tumor cells leads to cell cycle arrest in G2/M, mitochondrial perturbations, caspase activation, and apoptosis
physiological function
granzyme M induces the epithelial mesenchymal transition in cancer cells associated with STAT3 activation. It increases chemoresistance, colony formation, cytokine secretion and invasiveness
physiological function
the enzyme has a critical role in providing innate immune protection in ulcerative colitis. It has a critical role during early stages of inflammation in ulcerative colitis
physiological function
the enzyme is involved in killing of tumor cells and virally infected cells. It contributes to cytokine release and processing
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
33000 - 83000
-
SDS-PAGE, differentially glycosylated species in Pichia pastoris
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
-
first step requires cleavage of signal peptide resulting in an inactive zymogen with an amino-terminal activation propeptide, which must then be cleaved by another protease to generate a biologically active enzyme
additional information
additional information
post-translational modification, including O-glycosylation of serine, phosphorylation of serine and threonine and myristoylation of glycine, play an important role in the interaction of enzyme with the cell surface membrane and regulate protein trafficking and stability. Phosphorylated serine and threonine also plays a role in tumor elimination, viral clearance and tissue repair
additional information
-
post-translational modification, including O-glycosylation of serine, phosphorylation of serine and threonine and myristoylation of glycine, play an important role in the interaction of enzyme with the cell surface membrane and regulate protein trafficking and stability. Phosphorylated serine and threonine also plays a role in tumor elimination, viral clearance and tissue repair
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structures of wild-type hGzmM, the inactive D86N-GzmM mutant with bound peptide substrate, and the complexes with a catalytic product and with a tetrapeptide chloromethylketone inhibitor are solved to 1.96 A, 2.30 A, 2.17 A and 2.70 A, respectively
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D86N
K179M
-
reduced activity for substrate containing methionine at P1, acquired chymase activity for phenylalanine at P1
S201G
-
reduced activity for substrate containing methionine at P1, acquired chymase activity for phenylalanine at P1
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
D86N-GzmM cDNA inserted into the Gal4 DNA binding domain vector. pGBKT7-D86N-GzmM and pGADT7-survivin cotransformed into the yeast stain AH109. Active GzmM and inactive D86N-GzmM mutant expressed in Escherichia coli Rosetta (DE3) strain. Stable HeLa transfectants or Jurkat cells incubated with different concentrations of GzmM or mutant D86N-GzmM
subcloned from I.M.A.G.E. clone 112558 into vector pPiCza A for expression in Pichia pastoris
-
wild-type, mutant with deletion of a dipeptide and mutant with deletion of a hexapeptide, expressed in COS cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
CD4+ T cells hardly express GrM (only 4%). GrM protein expression is absent in non-T non-natural killer cells in peripheral blood mononuclear cells
granzyme M is expressed by lymphocytes of both the innate and adaptive immune system: high expression by natural killer cells, natural killer T cells, and gammadelta T cells (70-80% of cells). CD8+ T cells also express GrM (ca. 50% of cells) and comparing the naive to early effector-memory, to late effectormemory, to effector subset, this expression gradually increases during differentiation (in particular by the differentiated effector CD27- CD45RO- subset). GrM is usually co-expressed with perforin (ca. 60% of cells). In CD8+ T cells, about 90% of GrM positive cells also express GrB
GrM protein expression by lymphocyte populations is not significantly affected by a panel of GrB-inducing cytokines
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
medicine
granzymes are differentially expressed in distinct sub-populations of peripheral blood lymphocytes
medicine
granzyme M is expressed by human cytomegalovirus-specific CD8+ T cells both in latently infected healthy individuals and in transplant patients during primary human cytomegalovirus infection. Host cell heterogeneous nuclear ribonucleoprotein K is a physiological granzyme M substrate. Granzyme M most efficiently cleaves heterogeneous nuclear ribonucleoprotein K in the presence of RNA at multiple sites, thereby likely destroying heterogeneous nuclear ribonucleoprotein K function. Host cell heterogeneous nuclear ribonucleoprotein K is essential for hman cytomegalovirus replication not only by promoting viability of human cytomegalovirus-infected cells but predominantly by regulating viral immediate-early 2 protein levels. Granzyme M decreases viral immediate-early 2 protein expression in human cytomegalovirus-infected cells
medicine
use of granzyme M as an alternative component of human cytolytic fusion proteins. Upon fusion to the humanized single-chain antibody fragment (scFv) H22 which specifically binds to CD64, an FccRI receptor overexpressed on activated myeloid cells and leukemic cells, the humanized cytolytic fusion protein specifically targets the acute myeloid leukemia cell line HL60 in vitro and is cytotoxic with an IC50 between 1.2 and 6.4 nM. These findings are confirmed ex vivo using leukemic primary cells from patients, which are killed by granzyme M despite the presence of the granzyme B inhibitor serpin B9
medicine
-
GzmM initiates caspase-dependent apoptosis, induces DNA fragmentation, but not DNA nicking, Pro-Ject protein transfection reagent can efficiently transport GZmM into target cells
medicine
-
in the presence of perforin, the protease activity of GrM rapidly and effectively induces target cell death, but does not feature obvious DNA fragmentation, occurs independently of caspases, caspase activation, and perturbation of mitochondria
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Smyth, M.J.; O'Connor, M.D.; Kelly, J.M.; Ganesvaran, P.; Thia, K.Y.; Trapani, J.A.
Expression of recombinant human Met-ase-1: a NK cell-specific granzyme
Biochem. Biophys. Res. Commun.
217
675-683
1995
Homo sapiens
Sattar, R.; Ali, S.A.; Abbasi, A.
Bioinformatics of granzymes: sequence comparison and structural studies on granzyme family by homology modeling
Biochem. Biophys. Res. Commun.
308
726-735
2003
Homo sapiens
Smyth, M.J.; O'Connor, M.D.; Trapani, J.A.; Kershaw, M.H.; Brinkworth, R.I.
A novel substrate-binding pocket interaction restricts the specificity of the human NK cell-specific serine protease, Met-ase-1
J. Immunol.
156
4174-4181
1996
Homo sapiens
Bade, B.; Boettcher, H.E.; Lohrmann, J.; Hink-Schauer, C.; Bratke, K.; Jenne, D.E.; Virchow, J.C., Jr.; Luttmann, W.
Differential expression of the granzymes A, K and M and perforin in human peripheral blood lymphocytes
Int. Immunol.
17
1419-1428
2005
Homo sapiens (P51124)
Rukamp, B.J.; Kam, C.M.; Natarajan, S.; Bolton, B.W.; Smyth, M.J.; Kelly, J.M.; Powers, J.C.
Subsite specificities of granzyme M: a study of inhibitors and newly synthesized thiobenzyl ester substrates
Arch. Biochem. Biophys.
422
9-22
2004
Homo sapiens (P51124), Homo sapiens, Rattus norvegicus (Q03238)
Kelly, J.M.; Waterhouse, N.J.; Cretney, E.; Browne, K.A.; Ellis, S.; Trapani, J.A.; Smyth, M.J.
Granzyme M mediates a novel form of perforin-dependent cell death
J. Biol. Chem.
279
22236-22242
2004
Homo sapiens
Mahrus, S.; Kisiel, W.; Craik, C.S.
Granzyme M is a regulatory protease that inactivates proteinase inhibitor 9, an endogenous inhibitor of granzyme B
J. Biol. Chem.
279
54275-54282
2004
Homo sapiens
Lu, H.; Hou, Q.; Zhao, T.; Zhang, H.; Zhang, Q.; Wu, L.; Fan, Z.
Granzyme M directly cleaves inhibitor of caspase-activated DNase (CAD) to unleash CAD leading to DNA fragmentation
J. Immunol.
177
1171-1178
2006
Homo sapiens
Morice, W.G.; Jevremovic, D.; Hanson, C.A.
The expression of the novel cytotoxic protein granzyme M by large granular lymphocytic leukaemias of both T-cell and NK-cell lineage: an unexpected finding with implications regarding the pathobiology of these disorders
Br. J. Haematol.
137
237-239
2007
Homo sapiens
Hua, G.; Zhang, Q.; Fan, Z.
Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis
J. Biol. Chem.
282
20553-20560
2007
Homo sapiens (P51124)
Cullen, S.P.; Afonina, I.S.; Donadini, R.; Luethi, A.U.; Medema, J.P.; Bird, P.I.; Martin, S.J.
Nucleophosmin is cleaved and inactivated by the cytotoxic granule protease granzyme M during natural killer cell-mediated killing
J. Biol. Chem.
284
5137-5147
2009
Homo sapiens (P51124), Homo sapiens
Bovenschen, N.; de Koning, P.J.; Quadir, R.; Broekhuizen, R.; Damen, J.M.; Froelich, C.J.; Slijper, M.; Kummer, J.A.
NK cell protease granzyme M targets alpha-tubulin and disorganizes the microtubule network
J. Immunol.
180
8184-8191
2008
Homo sapiens (P51124), Homo sapiens
Wu, L.; Wang, L.; Hua, G.; Liu, K.; Yang, X.; Zhai, Y.; Bartlam, M.; Sun, F.; Fan, Z.
Structural basis for proteolytic specificity of the human apoptosis-inducing granzyme M
J. Immunol.
183
421-429
2009
Homo sapiens (P51124), Homo sapiens
Froelich, C.J.; Pardo, J.; Simon, M.M.
Granule-associated serine proteases: granzymes might not just be killer proteases
Trends Immunol.
30
117-123
2009
Mus musculus (O08643), Homo sapiens (P51124), Rattus norvegicus (Q03238)
Hu, D.; Liu, S.; Shi, L.; Li, C.; Wu, L.; Fan, Z.
Cleavage of survivin by Granzyme M triggers degradation of the survivin-X-linked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells
J. Biol. Chem.
285
18326-18335
2010
Homo sapiens (P51124)
Khurshid, R.; Saleem, M.; Akhtar, M.S.; Salim, A.
Granzyme M: Characterization with sites of post-translational modification and specific sites of interaction with substrates and inhibitors
Mol. Biol. Rep.
392
199-207
2010
Homo sapiens (P51124), Homo sapiens
de Koning, P.J.; Tesselaar, K.; Bovenschen, N.; Colak, S.; Quadir, R.; Volman, T.J.; Kummer, J.A.
The cytotoxic protease granzyme M is expressed by lymphocytes of both the innate and adaptive immune system
Mol. Immunol.
47
903-911
2010
Homo sapiens (P51124), Homo sapiens
De Poot, S.; Lai, K.; Hovingh, E.; Bovenschen, N.
Granzyme M cannot induce cell death via cleavage of mouse FADD
Apoptosis
18
533-534
2013
Homo sapiens (P51124), Mus musculus (O08643), Mus musculus
Schiffer, S.; Letzian, S.; Jost, E.; Mladenov, R.; Hristodorov, D.; Huhn, M.; Fischer, R.; Barth, S.; Thepen, T.
Granzyme M as a novel effector molecule for human cytolytic fusion proteins: CD64-specific cytotoxicity of Gm-H22(scFv) against leukemic cells
Cancer Lett.
341
178-185
2013
Homo sapiens (P51124), Homo sapiens
van Domselaar, R.; de Poot, S.A.; Remmerswaal, E.B.; Lai, K.W.; ten Berge, I.J.; Bovenschen, N.
Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication
Cell Death Differ.
20
419-429
2013
Homo sapiens (P51124), Homo sapiens
de Poot, S.A.; Lai, K.W.; van der Wal, L.; Plasman, K.; Van Damme, P.; Porter, A.C.; Gevaert, K.; Bovenschen, N.
Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis
Cell Death Differ.
21
416-426
2014
Homo sapiens (P51124), Homo sapiens
Souza-Fonseca-Guimaraes, F.; Krasnova, Y.; Putoczki, T.; Miles, K.; MacDonald, K.P.; Town, L.; Shi, W.; Gobe, G.C.; McDade, L.; Mielke, L.A.; Tye, H.; Masters, S.L.; Belz, G.T.; Huntington, N.D.; Radford-Smith, G.; Smyth, M.J.
Granzyme M has a critical role in providing innate immune protection in ulcerative colitis
Cell Death Dis.
7
e2302
2016
Homo sapiens (P51124), Homo sapiens
Wensink, A.C.; Wiewel, M.A.; Jongeneel, L.H.; Boes, M.; van der Poll, T.; Hack, C.E.; Bovenschen, N.
Granzyme M and K release in human experimental endotoxemia
Immunobiology
221
773-777
2016
Homo sapiens (P51124), Homo sapiens
Wang, H.; Sun, Q.; Wu, Y.; Wang, L.; Zhou, C.; Ma, W.; Zhang, Y.; Wang, S.; Zhang, S.
Granzyme M expressed by tumor cells promotes chemoresistance and EMT in vitro and metastasis in vivo associated with STAT3 activation
Oncotarget
6
5818-5831
2015
Homo sapiens (P51124), Homo sapiens, Mus musculus (O08643), Mus musculus
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