P58043 · SESN2_MOUSE
- ProteinSestrin-2
- GeneSesn2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids480 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex (PubMed:18692468, PubMed:25259925).
In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents mTORC1 signaling (PubMed:18692468, PubMed:25259925).
Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:18692468, PubMed:25259925).
This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses (By similarity).
May negatively regulate protein translation in response to endoplasmic reticulum stress, via mTORC1 (PubMed:24947615).
May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085).
May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress (PubMed:18692468).
Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (By similarity).
Was originally reported to contribute to oxidative stress resistance by reducing PRDX1. However, this could not be confirmed (By similarity).
In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents mTORC1 signaling (PubMed:18692468, PubMed:25259925).
Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:18692468, PubMed:25259925).
This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses (By similarity).
May negatively regulate protein translation in response to endoplasmic reticulum stress, via mTORC1 (PubMed:24947615).
May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085).
May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress (PubMed:18692468).
Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (By similarity).
Was originally reported to contribute to oxidative stress resistance by reducing PRDX1. However, this could not be confirmed (By similarity).
Catalytic activity
- a hydroperoxide + L-cysteinyl-[protein] = an alcohol + S-hydroxy-L-cysteinyl-[protein]This reaction proceeds in the forward direction.
Features
Showing features for active site, binding site.
GO annotations
Keywords
- Molecular function
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameSestrin-2
- EC number
Gene names
Organism names
- Organism
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionP58043
Proteomes
Organism-specific databases
Subcellular Location
Phenotypes & Variants
Disruption phenotype
Sesn2 knockout mice are fully viable and do not display any overt developmental abnormalities. When kept on high fat diet, they display higher insulin resistance and glucose intolerance (PubMed:22958918).
The oxidative stress induced by acute lipogenesis upon refeeding results in increased liver damages in the Sesn2 knockout mice. Any condition, like obesity, that triggers chronic or acute endoplasmic reticulum stresses have the same consequences in these mice and can lead to liver fibrosis (PubMed:23274085, PubMed:24947615).
Sesn2 and Sesn3 double knockout mice display insulin resistance and glucose intolerance (PubMed:22958918).
Triple knockout mice lacking Sesn1, Sesn2 and Sesn3 do not display an embryonic lethal phenotype since they are born at an expected Mendelian ratio. Moreover, they are not distinguishable from their wild-type littermates. However, their survival at 10 days is dramatically affected. This is associated with a constitutive activation of TORC1 signaling in the liver, heart and skeletal muscle during postnatal fasting, that occurs between birth and suckling (PubMed:25259925).
The oxidative stress induced by acute lipogenesis upon refeeding results in increased liver damages in the Sesn2 knockout mice. Any condition, like obesity, that triggers chronic or acute endoplasmic reticulum stresses have the same consequences in these mice and can lead to liver fibrosis (PubMed:23274085, PubMed:24947615).
Sesn2 and Sesn3 double knockout mice display insulin resistance and glucose intolerance (PubMed:22958918).
Triple knockout mice lacking Sesn1, Sesn2 and Sesn3 do not display an embryonic lethal phenotype since they are born at an expected Mendelian ratio. Moreover, they are not distinguishable from their wild-type littermates. However, their survival at 10 days is dramatically affected. This is associated with a constitutive activation of TORC1 signaling in the liver, heart and skeletal muscle during postnatal fasting, that occurs between birth and suckling (PubMed:25259925).
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 419 | Unable to inhibit TORC1 signaling; when associated with A-422 and A-426. | ||||
Sequence: R → A | ||||||
Mutagenesis | 422 | Unable to inhibit TORC1 signaling; when associated with A-419 and A-426. | ||||
Sequence: K → A | ||||||
Mutagenesis | 426 | Unable to inhibit TORC1 signaling; when associated with A-419 and A-422. | ||||
Sequence: K → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 33 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for modified residue, chain, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Modified residue | 1 | N-acetylmethionine | ||||
Sequence: M | ||||||
Chain | PRO_0000221182 | 1-480 | Sestrin-2 | |||
Sequence: MIVADSECHSEIKGYLPFTRGGVAGPETREEHREGQARRGSRGPSAFIPVEEILREGAESLEQHLGLEALMSSGRVDNLAVVMGLHPDYLSSFWRLHYLLLHTDGPLASSWRHYIAIMAAARHQCSYLVGSHMTEFLQTGGDPEWLLGLHRAPEKLRKLSEVNKLLAHRPWLITKEHIQALLKTGEHSWSLAELIQALVLLTHCHSLASFVFGCGILPEGDAEGSPASQAPSPPSEQGTPPSGDPLNNSGGFEAARDVEALMERMRQLQESLLRDEGASQEEMENRFELEKSESLLVTPSADILEPSPHPDILCFVEDPAFGYEDFTRRGTQAPPTFRAQDYTWEDHGYSLIQRLYPEGGQLLDEKFQVACSLTYNTIAMHSGVDTSMLRRAIWNYIHCVFGIRYDDYDYGEVNQLLERNLKIYIKTVACYPEKTTRRMYNLFWRHFRHSEKVHVNLLLLEARMQAALLYALRAITRYMT | ||||||
Cross-link | 175 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 249 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylated by ULK1 at multiple sites.
Ubiquitinated at Lys-175 by RNF167 via 'Lys-63'-linked polyubiquitination in response to leucine deprivation: ubiquitination promotes SESN2-interaction with the GATOR2 complex, leading to inhibit the TORC1 signaling pathway. Deubiquitinated at Lys-175 by STAMBPL1, promoting the TORC1 signaling pathway. Ubiquitinated by RNF186; ubiquitination mediates proteasomal degradation.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Detected in heart, liver and skeletal muscles (at protein level).
Induction
Up-regulated by treatments inducing endoplasmic reticulum stress.
Gene expression databases
Interaction
Subunit
Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (By similarity).
Conveys leucine availability via direct interaction with SEH1L and WDR24 components of the GATOR2 complex (By similarity).
Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925).
May interact with the TORC2 complex (PubMed:25377878).
Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1 (PubMed:25040165).
May also associate with the complex composed of TSC1, TSC2 and the AMP-responsive protein kinase/AMPK to regulate TORC1 signaling (PubMed:18692468).
May interact with PRDX1 (By similarity).
Conveys leucine availability via direct interaction with SEH1L and WDR24 components of the GATOR2 complex (By similarity).
Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925).
May interact with the TORC2 complex (PubMed:25377878).
Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1 (PubMed:25040165).
May also associate with the complex composed of TSC1, TSC2 and the AMP-responsive protein kinase/AMPK to regulate TORC1 signaling (PubMed:18692468).
May interact with PRDX1 (By similarity).
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 20-43 | Disordered | ||||
Sequence: RGGVAGPETREEHREGQARRGSRG | ||||||
Compositional bias | 25-39 | Basic and acidic residues | ||||
Sequence: GPETREEHREGQARR | ||||||
Region | 66-239 | N-terminal domain; mediates the alkylhydroperoxide reductase activity | ||||
Sequence: GLEALMSSGRVDNLAVVMGLHPDYLSSFWRLHYLLLHTDGPLASSWRHYIAIMAAARHQCSYLVGSHMTEFLQTGGDPEWLLGLHRAPEKLRKLSEVNKLLAHRPWLITKEHIQALLKTGEHSWSLAELIQALVLLTHCHSLASFVFGCGILPEGDAEGSPASQAPSPPSEQGT | ||||||
Region | 221-251 | Disordered | ||||
Sequence: DAEGSPASQAPSPPSEQGTPPSGDPLNNSGG | ||||||
Region | 272-291 | Disordered | ||||
Sequence: LLRDEGASQEEMENRFELEK | ||||||
Region | 308-480 | C-terminal domain; mediates TORC1 regulation | ||||
Sequence: PHPDILCFVEDPAFGYEDFTRRGTQAPPTFRAQDYTWEDHGYSLIQRLYPEGGQLLDEKFQVACSLTYNTIAMHSGVDTSMLRRAIWNYIHCVFGIRYDDYDYGEVNQLLERNLKIYIKTVACYPEKTTRRMYNLFWRHFRHSEKVHVNLLLLEARMQAALLYALRAITRYMT |
Domain
The N-terminal domain has an alkylhydroperoxide reductase activity.
The C-terminal domain mediates interaction with GATOR2 through which it regulates TORC1 signaling.
Sequence similarities
Belongs to the sestrin family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length480
- Mass (Da)54,377
- Last updated2001-04-27 v1
- Checksum11B1FF352E75C90F
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 25-39 | Basic and acidic residues | ||||
Sequence: GPETREEHREGQARR |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
BC005672 EMBL· GenBank· DDBJ | AAH05672.1 EMBL· GenBank· DDBJ | mRNA |