Information on EC 3.4.22.B71 - SENP2 peptidase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.22.B71
preliminary BRENDA-supplied EC number
RECOMMENDED NAME
GeneOntology No.
SENP2 peptidase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
The enzyme catalyzes two essential functions in the SUMO pathway: processing of full-length SUMO-1, SUMO-2 and SUMO-3 to their mature forms and deconjugation of SUMO1, SUMO2 and SUMO3 from targeted proteins. Deconjugates SUMO-2 from mitotic kinase Aurora-B. Deconjugates SUMO-1 from Mdm2, an protein critical for genome integrity in P53-dependent stress resüponse. Cleavage of Gly97-/-His98 bond in the SUMO-1 precursor with release of the propeptide His-Ser-Thr-Val. Cleavage of Gly93-/-Val94 bond in the SUMO-2 precursor with release of the propeptide Val94-Thyr. Cleavage of the Gly92-/-Val93 in the SUMO-3 precursor with release of the propeptide Pro-Glu-Ser-Ser-Leu-Ala-Gly-His-Ser-Phe.
show the reaction diagram
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(SUMO-1)-Mdm2 conjugate + H2O
SUMO + Mdm2
show the reaction diagram
(SUMO-1)-Ran GTPase-activating protein 1 conjugate + H2O
SUMO-1 + Ran GTPase-activating protein 1
show the reaction diagram
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-
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?
(SUMO-2)-Ran GTPase-activating protein 1 conjugate + H2O
SUMO-2 + Ran GTPase-activating protein 1
show the reaction diagram
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?
(SUMO-2/3)-Ran GTPase-activating protein 1 conjugate + H2O
SUMO-2/3 + Ran GTPase-activating protein 1
show the reaction diagram
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-
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?
(SUMO-3)-Ran GTPase-activating protein 1 conjugate + H2O
SUMO-3 + Ran GTPase-activating protein 1
show the reaction diagram
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?
acetyl-QTGG-7-amino-4-trifluoromethylcoumarin + H2O
acetyl-QTGG + 7-amino-4-trifluoromethylcoumarin
show the reaction diagram
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?
diSUMO2 + H2O
2 SUMO2
show the reaction diagram
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?
poly-SUMO-2/3-Aurora-B conjugate + H2O
?
show the reaction diagram
polySUMO2 + H2O
?
show the reaction diagram
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?
SUMO-1 precursor + H2O
SUMO-1 + His-Ser-Thr-Val
show the reaction diagram
SUMO-2 precursor + H2O
SUMO-2 + Val-Tyr
show the reaction diagram
SUMO-3 precursor + H2O
SUMO-3 + Val-Pro-Glu-Ser-Ser-Leu-Ala-Gly-His-Ser-Phe
show the reaction diagram
SUMO-C/EBPbeta + H2O
SUMO + C/EBPbeta
show the reaction diagram
SUMO-Mdm2 conjugate + H2O
SUMO + Mdm2
show the reaction diagram
SUMO-Pc2/CBX4 conjugate + H2O
SUMO + Pc2/CBX4
show the reaction diagram
SUMO-Ran GTPase-activating protein 1 conjugate + H2O
?
show the reaction diagram
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SENP2 exhibits substantially higher isopeptidase than endopeptidase activity
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SUMOylated myocyte-specific enhancer factor-2A + H2O
deSUMOylated myocyte-specific enhancer factor-2A + SUMO
show the reaction diagram
additional information
?
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nucleoporin Nup153 binds to SENP2 by interacting with the unique N-terminal domain of Nup153 as well as a specific region within the C-terminal FG-rich region. Nup153 is a substrate for SUMOylation, with this modification kept in check by the SUMO protease
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(SUMO-1)-Mdm2 conjugate + H2O
SUMO + Mdm2
show the reaction diagram
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SUMO conjugation of Mdm2 induces its co-localization and association with SENP2 at the PML bodies. SENP2 catalyzes the desumoylation process of Mdm2. SENP2 mediated regulation of Mdm2 critical for genome integrity in p53-dependent stress responses
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poly-SUMO-2/3-Aurora-B conjugate + H2O
?
show the reaction diagram
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specifically deconjugates SUMO from mitotic kinase Aurora-B. Lys202 on human Aurora-B is preferentially modified by SUMO, and enhancement of SUMOylation in cells facilitates Aurora-B autophosphorylation, which is essential for its activation. Conversely, SENP2-mediated deSUMOylation of Aurora-B down-regulates its autophosphorylation in cells and also impairs its re-activation in Aurora inhibitor VX-680-treated mitotic cells. Poly-SUMO-2 conjugation of Aurora-B occurs during the M phase ofthe cell cycle, and both SUMO-2 and PIAS3 are localized adjacent to Aurora-B in the kinetochores in early mitosis. Aurora-B is a mitotic SUMO substrate and its kinase activity is fine-tuned by the SUMO system
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SUMO-C/EBPbeta + H2O
SUMO + C/EBPbeta
show the reaction diagram
Q91ZX6
sumoylation causes destabilization of the C/EBPbeta protein and that this process can be reversed by SENP2
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SUMO-Mdm2 conjugate + H2O
SUMO + Mdm2
show the reaction diagram
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Mdm2 is an important negative regulator of the p53 tumor suppressor. The SENP2 mediated SUMO modification of Mdm2 appears to be crucial for its subcellular trafficking
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SUMO-Pc2/CBX4 conjugate + H2O
SUMO + Pc2/CBX4
show the reaction diagram
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Pc2/CBX4 is a polycomb repressive complex 1 (PRC1) subunit. SENP2 specifically controls Pc2/CBX4 contained PRC1 activity through regulation of the SUMOylation status of Pc2/CBX4, which facilitates its binding to H3K27me3 in mammalian cells to mediate transcriptional repression
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SUMOylated myocyte-specific enhancer factor-2A + H2O
deSUMOylated myocyte-specific enhancer factor-2A + SUMO
show the reaction diagram
additional information
?
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nucleoporin Nup153 binds to SENP2 by interacting with the unique N-terminal domain of Nup153 as well as a specific region within the C-terminal FG-rich region. Nup153 is a substrate for SUMOylation, with this modification kept in check by the SUMO protease
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
SUMO
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SUMO domain enhances catalysis of SENP2, substrate induced activation
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00547
(SUMO-1)-Ran GTPase-activating protein 1 conjugate
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pH 8.0, 23°C
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0.033
(SUMO-2/3)-Ran GTPase-activating protein 1 conjugate
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pH 8.0, 23°C
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0.0279
SUMO-1 precursor
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pH 8.0, 23°C
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0.002
SUMO-2 precursor
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pH 8.0, 23°C
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0.0022
SUMO-3 precursor
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pH 8.0, 23°C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
31
(SUMO-1)-Ran GTPase-activating protein 1 conjugate
Homo sapiens
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pH 8.0, 23°C
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50.5
(SUMO-2/3)-Ran GTPase-activating protein 1 conjugate
Homo sapiens
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pH 8.0, 23°C
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0.72
SUMO-1 precursor
Homo sapiens
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pH 8.0, 23°C
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0.77
SUMO-2 precursor
Homo sapiens
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pH 8.0, 23°C
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0.11
SUMO-3 precursor
Homo sapiens
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pH 8.0, 23°C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5667
(SUMO-1)-Ran GTPase-activating protein 1 conjugate
Homo sapiens
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pH 8.0, 23°C
41707
153
(SUMO-2/3)-Ran GTPase-activating protein 1 conjugate
Homo sapiens
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pH 8.0, 23°C
41708
25.8
SUMO-1 precursor
Homo sapiens
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pH 8.0, 23°C
19535
385
SUMO-2 precursor
Homo sapiens
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pH 8.0, 23°C
19536
5
SUMO-3 precursor
Homo sapiens
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pH 8.0, 23°C
41706
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.6
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assay at
8
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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the enzyme is down-regulated in bladder cancer samples
Manually annotated by BRENDA team
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brain
Manually annotated by BRENDA team
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weak expression, benign breast adenofibroma cell and malignant breast cancer tissue
Manually annotated by BRENDA team
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isolated from skeletal muscle
Manually annotated by BRENDA team
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SENP2 is highly expressed in trophoblast cells that are required for placentation
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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SENP2 shuttles between the nucleus and the cytoplasm. Identification of a bipartite nuclear localization signal and a CRM1-dependent nuclear export signal in the SUMO protease SENP2. Nucleocytoplasmic shuttling is a crucial regulatory mechanism for SENP2 function
Manually annotated by BRENDA team
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ubiquitination
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SENP2 can be polyubiquitinated in vivo and degraded through proteolysis. Restricting SENP2 in the nucleus by mutations in the nuclear export signal (NES) impairs its polyubiquitination, whereas a cytoplasm-localized SENP2 made by introducing mutations in the nuclear localization signal (NLS) can be efficiently polyubiquitinated, suggesting that SENP2 is ubiquitinated in the cytoplasm
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant chimeric mutant SENP2 C548S-loop1 in complex with SUMO2, X-ray diffraction structure determination and analysis at 2.15 A resolution
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Senp2 crystallization is performed at 4°C using sitting and hanging drop vapor diffusion methods. X-ray structures of Senp2 catalytic protease domain and of a covalent thiohemiacetal transition-state complex obtained between the Senp2 catalytic domain and SUMO-1 reveales details of the respective protease and substrate surfaces utilized in interactions between these two proteins. Comparative biochemical and structural analysis between Senp2 and the yeast SUMO protease Ulp1 reveales differential abilities to process SUMO-1, SUMO-2, and SUMO-3 in maturation and deconjugation reactions
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X-ray structures are determined for a catalytically inert SENP2 protease domain in complex with conjugated RanGAP1-SUMO-1 or RanGAP1-SUMO-2, or in complex with SUMO-2 or SUMO-3 precursors
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
catalytic C-terminal domain of human SENP2(364–489) expressed in Escherichia coli
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catalytic domains of SENP2 expressed in Escherichia coli BL21 (DE3) as N-terminal His-tagged proteins
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recombinant chimeric mutant SENP2 C548S-loop1 in complex with SUMO2 by gel filtration
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of catalytic domains of SENP2 in Escherichia coli BL21 (DE3) as N-terminal His-tagged proteins
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expression of GFP-tagged SENP2 in HeLa cells
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gene SP2, recombinant expression of GFP-tagged or untagged SENP2 and the catalytically dead enzyme mutant transiently in HeLa cells
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recombinant expression of FLAG-tagged enzyme in HEK-293T cells
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the catalytic C-terminal domain of human SENP2(364-489) is expressed from pET28b in Escherichia coli BL21(DE3) codon-plus cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
in C2C12 myotubes, treatment with saturated fatty acids, like palmitate, leads to nuclear factor-kappaB-mediated increase in the expression of SENP2
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SENP2 expression is markedly increased upon the induction of adipocyte differentiation, and this increase is dependent on protein kinase A activation. Elevated cAMP level induces SENP2 expression through cyclic AMP response element-binding protein (CREB) binding to a functional cis-acting cAMP response element (CRE) in the SENP2 promoter
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the SENP2 level is not sensitive to changes in nucleoporin Nup153 abundance
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C548S
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site-directed mutagenesis, active site mutant
C549A
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catalytically inactive mutant
F393G/K394G
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construction of a chimeric enzyme SENP2 mutant with the insertion of loop1 from SENP6 into its sequence causing mutation of F393G/K394G, loop1 insertion is a determinant for SUMO2/3 activity and specificity, structure of SENP2-loop1 in complex with SUMO2, overview. The mutant reveals the details of an interface exclusive to SENP6/7 and the formation of unique contacts between both proteins, and the mutant shows an increase of the proteolytic activity for diSUMO2 and polySUMO2 substrates. The chimeric insertion mutant used for crystallization studies is also mutated at active site residue, C548S, for a stable complex formation
G545D
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slight decrease in SUMO-1 processing activity and SUMO-2 processing activity. Decrease in cleavage of the RanGAP1-SUMO-1 conjugate
G545F
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decrease in SUMO-1 processing activitya and SUMO-2 processing activity. Increase in SUMO-3 procesing activity
G545S
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decrease in SUMO-1 processing activity, SUMO-2 processing activity and SUMO-3 procesing activity. Decrease in cleavage of the RanGAP1-SUMO-1 conjugate
M497A
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increase in SUMO-1 processing activity and SUMO-3 procesing activity. Decrease in cleavage of the RanGAP1-SUMO-1 conjugate. Slight decrease in cleavage of the RanGAP1-SUMO-2/3 conjugate
M497L
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decrease in SUMO-1 processing activity, SUMO-2 processing activity and SUMO-3 procesing activity
M497N
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slight increase in SUMO-1 processing activity, decrease in SUMO-2 processing activity. Decrease in cleavage of the RanGAP1-SUMO-1 conjugate
M497Q
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decrease in SUMO-1 processing activity, SUMO-2 processing activity and SUMO-3 procesing activity. Decrease in cleavage of the RanGAP1-SUMO-1 conjugate. Decrease in cleavage of the RanGAP1-SUMO-2/3 conjugate
R576L/K577M
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the catalytically inactive enzyme mutant SENP2Cat cannot regulate MMP13
V477A
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substitution results in mild effects on processing or deconjugation
C548S
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catalytically inactive mutant
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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muscle enzyme SENP2 can be a therapeutic target for the treatment of obesity-linked metabolic disorders