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Protein

Sestrin-2

Gene

SESN2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26612684, PubMed:26586190). Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:26449471, PubMed:26586190). 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 (PubMed:26612684). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (PubMed:19113821).10 Publications

Catalytic activityi

2 R'-SH + ROOH = R'-S-S-R' + H2O + ROH.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei125Cysteine sulfenic acid (-SOH) intermediate1 Publication1
Binding sitei386Leucine; via carbonyl oxygenCombined sources1 Publication1
Binding sitei451LeucineCombined sources1 Publication1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionOxidoreductase

Enzyme and pathway databases

ReactomeiR-HSA-5628897 TP53 Regulates Metabolic Genes
SIGNORiP58004

Names & Taxonomyi

Protein namesi
Recommended name:
Sestrin-2Curated (EC:1.11.1.151 Publication)
Alternative name(s):
Hypoxia-induced gene1 Publication
Gene namesi
Name:SESN2Imported
Synonyms:Hi951 Publication, SEST21 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000130766.4
HGNCiHGNC:20746 SESN2
MIMi607767 gene
neXtProtiNX_P58004

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi86H → A: Loss of leucine-binding. 1 Publication1
Mutagenesisi87P → S: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi113H → E: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with C-128. 1 Publication1
Mutagenesisi125C → S: Decreased alkylhydroperoxide reductase activity and loss of the ability to decrease intracellular reactive oxygen species. No effect on interaction with the GATOR2 complex. No effect on inhibition of TOR signaling. 3 Publications1
Mutagenesisi127Y → F: Decreased alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi128L → C: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with E-113. 1 Publication1
Mutagenesisi132H → A: Decreased alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi190S → W: Loss of interaction with GATOR2. No effect on leucine-binding. Unable to mediate leucine-induced inhibition of the TORC1 signaling pathway. 1 Publication1
Mutagenesisi204C → S: No effect on alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi214C → S: No effect on alkylhydroperoxide reductase activity. 1 Publication1
Mutagenesisi258V → R: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with L-259 and R-261. 1 Publication1
Mutagenesisi259E → L: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with R-258 and R-261. 1 Publication1
Mutagenesisi261L → A: Decreased leucine-binding. 1 Publication1
Mutagenesisi261L → R: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with R-258 and L-259. 1 Publication1
Mutagenesisi262 – 264MER → LMM: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication3
Mutagenesisi264R → P: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi314C → S: No effect on ability to decrease intracellular reactive oxygen species. 1 Publication1
Mutagenesisi336 – 337TF → AA: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication2
Mutagenesisi340 – 341QD → AA: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication2
Mutagenesisi373L → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-376. 1 Publication1
Mutagenesisi374T → A: Loss of leucine-binding. Constitutively interacts with the GATOR2 complex. 1 Publication1
Mutagenesisi375Y → A: Loss of leucine-binding. 1 Publication1
Mutagenesisi376N → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-373. 1 Publication1
Mutagenesisi385D → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-387. 1 Publication1
Mutagenesisi386T → A: Loss of leucine-binding. Constitutively interacts with the GATOR2 complex. 1 Publication1
Mutagenesisi387S → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-385. 1 Publication1
Mutagenesisi390R → A: Loss of leucine-binding. Constitutively interacts with the GATOR2 complex. 1 Publication1
Mutagenesisi399C → S: No effect on alkylhydroperoxide reductase activity. Altered ability to decrease intracellular reactive oxygen species. No effect on the ability to inhibit the TORC1 signaling pathway. 2 Publications1
Mutagenesisi406 – 407DD → AA: Loss of interaction with the GATOR2 complex. No effect on leucine-binding. 1 Publication2
Mutagenesisi406D → A: No effect on alkylhydroperoxide reductase activity. Loss of interaction with the GATOR2 complex. Unable to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi407D → A: No effect on alkylhydroperoxide reductase activity. Loss of interaction with the GATOR2 complex. Unable to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi409D → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-411 and A-415. 1 Publication1
Mutagenesisi411G → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-409 and A-415. 1 Publication1
Mutagenesisi415Q → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-409 and A-411. 1 Publication1
Mutagenesisi419R → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-422 and A-426. 1 Publication1
Mutagenesisi422K → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-419 and A-426. 1 Publication1
Mutagenesisi426K → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-419 and A-422. 1 Publication1
Mutagenesisi430C → S: No effect on alkylhydroperoxide reductase activity. Altered ability to decrease intracellular reactive oxygen species. No effect on the ability to inhibit the TORC1 signaling pathway. 2 Publications1
Mutagenesisi444W → E: Loss of leucine-binding. 1 Publication1
Mutagenesisi444W → L: Decreased affinity for leucine. Requires increased leucine concentration to dissociate from GATOR2 and activate TORC1 signaling. 1 Publication1
Mutagenesisi451E → A: Decreased leucine-binding. 1 Publication1
Mutagenesisi451E → Q: Loss of leucine-binding. Constitutively interacts with the GATOR2 complex. 1 Publication1

Organism-specific databases

DisGeNETi83667
OpenTargetsiENSG00000130766
PharmGKBiPA134882791

Polymorphism and mutation databases

BioMutaiSESN2
DMDMi13633882

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002211811 – 480Sestrin-2Add BLAST480

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1
Modified residuei249PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated by ULK1 at multiple sites.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP58004
MaxQBiP58004
PaxDbiP58004
PeptideAtlasiP58004
PRIDEiP58004
ProteomicsDBi57043

PTM databases

iPTMnetiP58004
PhosphoSitePlusiP58004

Expressioni

Tissue specificityi

Widely expressed.1 Publication

Inductioni

Up-regulated by hypoxia and DNA damage (PubMed:12203114). Up-regulated by treatments inducing endoplasmic reticulum stress (PubMed:24947615).2 Publications

Gene expression databases

BgeeiENSG00000130766 Expressed in 187 organ(s), highest expression level in kidney epithelium
CleanExiHS_SESN2
GenevisibleiP58004 HS

Organism-specific databases

HPAiHPA018191

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 (PubMed:25263562, PubMed:25457612, PubMed:26449471). 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 (By similarity). Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1 (PubMed:23274085, 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 (PubMed:15105503).By similarity8 Publications

Binary interactionsi

Protein-protein interaction databases

BioGridi123724, 14 interactors
DIPiDIP-62044N
IntActiP58004, 17 interactors
MINTiP58004
STRINGi9606.ENSP00000253063

Structurei

Secondary structure

1480
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP58004
SMRiP58004
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni66 – 239N-terminal domain; mediates the alkylhydroperoxide reductase activity1 PublicationAdd BLAST174
Regioni308 – 480C-terminal domain; mediates TORC1 regulation1 PublicationAdd BLAST173
Regioni374 – 377Leucine-bindingCombined sources1 Publication4

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.1 Publication

Sequence similaritiesi

Belongs to the sestrin family.Curated

Phylogenomic databases

eggNOGiKOG3746 Eukaryota
ENOG410XP7Z LUCA
GeneTreeiENSGT00440000040103
HOGENOMiHOG000232949
HOVERGENiHBG054648
InParanoidiP58004
KOiK20394
OMAiASSWRHY
OrthoDBiEOG091G0IVA
PhylomeDBiP58004
TreeFamiTF314230

Family and domain databases

Gene3Di1.20.1290.10, 1 hit
InterProiView protein in InterPro
IPR029032 AhpD-like
IPR006730 Sestrin
PANTHERiPTHR12474 PTHR12474, 1 hit
PfamiView protein in Pfam
PF04636 PA26, 1 hit
SUPFAMiSSF69118 SSF69118, 1 hit

Sequencei

Sequence statusi: Complete.

P58004-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MIVADSECRA ELKDYLRFAP GGVGDSGPGE EQRESRARRG PRGPSAFIPV
60 70 80 90 100
EEVLREGAES LEQHLGLEAL MSSGRVDNLA VVMGLHPDYF TSFWRLHYLL
110 120 130 140 150
LHTDGPLASS WRHYIAIMAA ARHQCSYLVG SHMAEFLQTG GDPEWLLGLH
160 170 180 190 200
RAPEKLRKLS EINKLLAHRP WLITKEHIQA LLKTGEHTWS LAELIQALVL
210 220 230 240 250
LTHCHSLSSF VFGCGILPEG DADGSPAPQA PTPPSEQSSP PSRDPLNNSG
260 270 280 290 300
GFESARDVEA LMERMQQLQE SLLRDEGTSQ EEMESRFELE KSESLLVTPS
310 320 330 340 350
ADILEPSPHP DMLCFVEDPT FGYEDFTRRG AQAPPTFRAQ DYTWEDHGYS
360 370 380 390 400
LIQRLYPEGG QLLDEKFQAA YSLTYNTIAM HSGVDTSVLR RAIWNYIHCV
410 420 430 440 450
FGIRYDDYDY GEVNQLLERN LKVYIKTVAC YPEKTTRRMY NLFWRHFRHS
460 470 480
EKVHVNLLLL EARMQAALLY ALRAITRYMT
Length:480
Mass (Da):54,494
Last modified:April 27, 2001 - v1
Checksum:i9C13371316D84060
GO

Sequence cautioni

The sequence BAB55438 differs from that shown. Reason: Erroneous initiation.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_022101320T → A. Corresponds to variant dbSNP:rs2274848Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY123223 mRNA Translation: AAM92261.1
AL136551 mRNA Translation: CAB66486.1
AK027896 mRNA Translation: BAB55438.1 Different initiation.
AK025640 mRNA No translation available.
AK315710 mRNA Translation: BAG38070.1
AL353622 Genomic DNA No translation available.
CH471059 Genomic DNA Translation: EAX07703.1
BC013304 mRNA Translation: AAH13304.1
BC033719 mRNA Translation: AAH33719.1
CCDSiCCDS321.1
RefSeqiNP_113647.1, NM_031459.4
UniGeneiHs.469543

Genome annotation databases

EnsembliENST00000253063; ENSP00000253063; ENSG00000130766
ENST00000645231; ENSP00000496365; ENSG00000285069
GeneIDi83667
KEGGihsa:83667
UCSCiuc001bps.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY123223 mRNA Translation: AAM92261.1
AL136551 mRNA Translation: CAB66486.1
AK027896 mRNA Translation: BAB55438.1 Different initiation.
AK025640 mRNA No translation available.
AK315710 mRNA Translation: BAG38070.1
AL353622 Genomic DNA No translation available.
CH471059 Genomic DNA Translation: EAX07703.1
BC013304 mRNA Translation: AAH13304.1
BC033719 mRNA Translation: AAH33719.1
CCDSiCCDS321.1
RefSeqiNP_113647.1, NM_031459.4
UniGeneiHs.469543

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5CUFX-ray3.50A/B/C/D/E1-480[»]
5DJ4X-ray2.70A/B/C/D/E1-480[»]
5T0NX-ray3.00A/B/C/D/E1-480[»]
ProteinModelPortaliP58004
SMRiP58004
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi123724, 14 interactors
DIPiDIP-62044N
IntActiP58004, 17 interactors
MINTiP58004
STRINGi9606.ENSP00000253063

PTM databases

iPTMnetiP58004
PhosphoSitePlusiP58004

Polymorphism and mutation databases

BioMutaiSESN2
DMDMi13633882

Proteomic databases

EPDiP58004
MaxQBiP58004
PaxDbiP58004
PeptideAtlasiP58004
PRIDEiP58004
ProteomicsDBi57043

Protocols and materials databases

DNASUi83667
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000253063; ENSP00000253063; ENSG00000130766
ENST00000645231; ENSP00000496365; ENSG00000285069
GeneIDi83667
KEGGihsa:83667
UCSCiuc001bps.4 human

Organism-specific databases

CTDi83667
DisGeNETi83667
EuPathDBiHostDB:ENSG00000130766.4
GeneCardsiSESN2
HGNCiHGNC:20746 SESN2
HPAiHPA018191
MIMi607767 gene
neXtProtiNX_P58004
OpenTargetsiENSG00000130766
PharmGKBiPA134882791
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3746 Eukaryota
ENOG410XP7Z LUCA
GeneTreeiENSGT00440000040103
HOGENOMiHOG000232949
HOVERGENiHBG054648
InParanoidiP58004
KOiK20394
OMAiASSWRHY
OrthoDBiEOG091G0IVA
PhylomeDBiP58004
TreeFamiTF314230

Enzyme and pathway databases

ReactomeiR-HSA-5628897 TP53 Regulates Metabolic Genes
SIGNORiP58004

Miscellaneous databases

ChiTaRSiSESN2 human
GeneWikiiSESN2
GenomeRNAii83667
PROiPR:P58004
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000130766 Expressed in 187 organ(s), highest expression level in kidney epithelium
CleanExiHS_SESN2
GenevisibleiP58004 HS

Family and domain databases

Gene3Di1.20.1290.10, 1 hit
InterProiView protein in InterPro
IPR029032 AhpD-like
IPR006730 Sestrin
PANTHERiPTHR12474 PTHR12474, 1 hit
PfamiView protein in Pfam
PF04636 PA26, 1 hit
SUPFAMiSSF69118 SSF69118, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSESN2_HUMAN
AccessioniPrimary (citable) accession number: P58004
Secondary accession number(s): Q5T7D0, Q96SI5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: April 27, 2001
Last modified: October 10, 2018
This is version 149 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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