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Protein

Sestrin-2

Gene

Sesn2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling. 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. May negatively regulate protein translation in response to endoplasmic reticulum stress, via TORC1 (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). Has an 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 (By similarity). However, this could not be confirmed (By similarity).By similarity4 Publications

Catalytic activityi

2 R'-SH + ROOH = R'-S-S-R' + H2O + ROH.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei125Cysteine sulfenic acid (-SOH) intermediateBy similarity1
Binding sitei386Leucine; via carbonyl oxygenBy similarity1
Binding sitei451LeucineBy similarity1

GO - Molecular functioni

GO - Biological processi

  • autophagy Source: MGI
  • cellular response to amino acid stimulus Source: UniProtKB
  • cellular response to leucine Source: UniProtKB
  • cellular response to oxidative stress Source: UniProtKB
  • DNA damage response, signal transduction by p53 class mediator Source: UniProtKB
  • fatty acid beta-oxidation Source: MGI
  • glucose homeostasis Source: MGI
  • glucose import Source: MGI
  • mitochondrial DNA metabolic process Source: MGI
  • mitochondrion organization Source: MGI
  • negative regulation of cell growth Source: UniProtKB
  • negative regulation of TORC1 signaling Source: UniProtKB
  • negative regulation of translation in response to endoplasmic reticulum stress Source: UniProtKB
  • positive regulation of macroautophagy Source: UniProtKB
  • positive regulation of protein localization to nucleus Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: UniProtKB
  • protein kinase B signaling Source: MGI
  • reactive oxygen species metabolic process Source: UniProtKB
  • regulation of cAMP-dependent protein kinase activity Source: MGI
  • regulation of gluconeogenesis involved in cellular glucose homeostasis Source: MGI
  • regulation of protein phosphorylation Source: MGI
  • regulation of response to reactive oxygen species Source: InterPro
  • response to glucose Source: MGI
  • response to insulin Source: MGI
  • triglyceride homeostasis Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Enzyme and pathway databases

ReactomeiR-MMU-5628897. TP53 Regulates Metabolic Genes.

Names & Taxonomyi

Protein namesi
Recommended name:
Sestrin-2Curated (EC:1.11.1.15By similarity)
Gene namesi
Name:Sesn2Imported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:2651874. Sesn2.

Subcellular locationi

  • Cytoplasm By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Disruption phenotypei

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).4 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi419R → A: Unable to inhibit TORC1 signaling; when associated with A-422 and A-426. 1 Publication1
Mutagenesisi422K → A: Unable to inhibit TORC1 signaling; when associated with A-419 and A-426. 1 Publication1
Mutagenesisi426K → A: Unable to inhibit TORC1 signaling; when associated with A-419 and A-422. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002211821 – 480Sestrin-2Add BLAST480

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineBy similarity1
Modified residuei249PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated by ULK1 at multiple sites.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP58043.
MaxQBiP58043.
PaxDbiP58043.
PRIDEiP58043.

PTM databases

iPTMnetiP58043.
PhosphoSitePlusiP58043.

Expressioni

Tissue specificityi

Detected in heart, liver and skeletal muscles (at protein level).1 Publication

Inductioni

Up-regulated by treatments inducing endoplasmic reticulum stress.1 Publication

Gene expression databases

BgeeiENSMUSG00000028893.
CleanExiMM_SESN2.
GenevisibleiP58043. MM.

Interactioni

Subunit structurei

Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (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).By similarity4 Publications

Protein-protein interaction databases

BioGridi231026. 38 interactors.
IntActiP58043. 38 interactors.
STRINGi10090.ENSMUSP00000030724.

Structurei

3D structure databases

ProteinModelPortaliP58043.
SMRiP58043.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni66 – 239N-terminal domain; mediates the alkylhydroperoxide reductase activityBy similarityAdd BLAST174
Regioni308 – 480C-terminal domain; mediates TORC1 regulationBy similarityAdd BLAST173
Regioni374 – 377Leucine-bindingBy similarity4

Domaini

Composed of an N-terminal domain that has an alkylhydroperoxide reductase activity and a C-terminal domain that mediates interaction with GATOR2 through which it regulates TORC1 signaling.By similarity

Sequence similaritiesi

Belongs to the sestrin family.Curated

Phylogenomic databases

eggNOGiKOG3746. Eukaryota.
ENOG410XP7Z. LUCA.
GeneTreeiENSGT00440000040103.
HOGENOMiHOG000232949.
HOVERGENiHBG054648.
InParanoidiP58043.
KOiK20394.
OMAiASSWRHY.
OrthoDBiEOG091G0IVA.
PhylomeDBiP58043.
TreeFamiTF314230.

Family and domain databases

Gene3Di1.20.1290.10. 1 hit.
InterProiIPR029032. AhpD-like.
IPR006730. Sestrin.
[Graphical view]
PfamiPF04636. PA26. 1 hit.
[Graphical view]
SUPFAMiSSF69118. SSF69118. 1 hit.

Sequencei

Sequence statusi: Complete.

P58043-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MIVADSECHS EIKGYLPFTR GGVAGPETRE EHREGQARRG SRGPSAFIPV
60 70 80 90 100
EEILREGAES LEQHLGLEAL MSSGRVDNLA VVMGLHPDYL SSFWRLHYLL
110 120 130 140 150
LHTDGPLASS WRHYIAIMAA ARHQCSYLVG SHMTEFLQTG GDPEWLLGLH
160 170 180 190 200
RAPEKLRKLS EVNKLLAHRP WLITKEHIQA LLKTGEHSWS LAELIQALVL
210 220 230 240 250
LTHCHSLASF VFGCGILPEG DAEGSPASQA PSPPSEQGTP PSGDPLNNSG
260 270 280 290 300
GFEAARDVEA LMERMRQLQE SLLRDEGASQ EEMENRFELE KSESLLVTPS
310 320 330 340 350
ADILEPSPHP DILCFVEDPA FGYEDFTRRG TQAPPTFRAQ DYTWEDHGYS
360 370 380 390 400
LIQRLYPEGG QLLDEKFQVA CSLTYNTIAM HSGVDTSMLR RAIWNYIHCV
410 420 430 440 450
FGIRYDDYDY GEVNQLLERN LKIYIKTVAC YPEKTTRRMY NLFWRHFRHS
460 470 480
EKVHVNLLLL EARMQAALLY ALRAITRYMT
Length:480
Mass (Da):54,377
Last modified:April 27, 2001 - v1
Checksum:i11B1FF352E75C90F
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC005672 mRNA. Translation: AAH05672.1.
CCDSiCCDS18726.1.
RefSeqiNP_659156.1. NM_144907.1.
UniGeneiMm.23608.

Genome annotation databases

EnsembliENSMUST00000030724; ENSMUSP00000030724; ENSMUSG00000028893.
GeneIDi230784.
KEGGimmu:230784.
UCSCiuc008vbj.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC005672 mRNA. Translation: AAH05672.1.
CCDSiCCDS18726.1.
RefSeqiNP_659156.1. NM_144907.1.
UniGeneiMm.23608.

3D structure databases

ProteinModelPortaliP58043.
SMRiP58043.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi231026. 38 interactors.
IntActiP58043. 38 interactors.
STRINGi10090.ENSMUSP00000030724.

PTM databases

iPTMnetiP58043.
PhosphoSitePlusiP58043.

Proteomic databases

EPDiP58043.
MaxQBiP58043.
PaxDbiP58043.
PRIDEiP58043.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000030724; ENSMUSP00000030724; ENSMUSG00000028893.
GeneIDi230784.
KEGGimmu:230784.
UCSCiuc008vbj.1. mouse.

Organism-specific databases

CTDi83667.
MGIiMGI:2651874. Sesn2.

Phylogenomic databases

eggNOGiKOG3746. Eukaryota.
ENOG410XP7Z. LUCA.
GeneTreeiENSGT00440000040103.
HOGENOMiHOG000232949.
HOVERGENiHBG054648.
InParanoidiP58043.
KOiK20394.
OMAiASSWRHY.
OrthoDBiEOG091G0IVA.
PhylomeDBiP58043.
TreeFamiTF314230.

Enzyme and pathway databases

ReactomeiR-MMU-5628897. TP53 Regulates Metabolic Genes.

Miscellaneous databases

PROiP58043.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000028893.
CleanExiMM_SESN2.
GenevisibleiP58043. MM.

Family and domain databases

Gene3Di1.20.1290.10. 1 hit.
InterProiIPR029032. AhpD-like.
IPR006730. Sestrin.
[Graphical view]
PfamiPF04636. PA26. 1 hit.
[Graphical view]
SUPFAMiSSF69118. SSF69118. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiSESN2_MOUSE
AccessioniPrimary (citable) accession number: P58043
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: April 27, 2001
Last modified: November 30, 2016
This is version 99 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.