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Protein

Sestrin-1

Gene

SESN1

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. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:25263562, PubMed:26449471). This stress-inducible metabolic regulator may also play a role in protection against oxidative and genotoxic stresses (By similarity). 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 have 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 (PubMed:15105503). 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 sitei130Cysteine sulfenic acid (-SOH) intermediateBy similarity1
Binding sitei398Leucine; via carbonyl oxygenBy similarity1
Binding sitei463LeucineBy similarity1

GO - Molecular functioni

  • leucine binding Source: UniProtKB
  • peroxiredoxin activity Source: UniProtKB-EC

GO - Biological processi

  • cellular oxidant detoxification Source: UniProtKB
  • cellular response to amino acid starvation Source: UniProtKB
  • cellular response to glucose starvation Source: UniProtKB
  • negative regulation of TORC1 signaling Source: UniProtKB
  • reactive oxygen species metabolic process Source: UniProtKB
  • regulation of response to reactive oxygen species Source: InterPro

Keywordsi

Molecular functionOxidoreductase

Enzyme and pathway databases

ReactomeiR-HSA-5628897 TP53 Regulates Metabolic Genes
SIGNORiQ9Y6P5

Names & Taxonomyi

Protein namesi
Recommended name:
Sestrin-1Curated (EC:1.11.1.15By similarity)
Alternative name(s):
p53-regulated protein PA261 Publication
Gene namesi
Name:SESN1Imported
Synonyms:PA261 Publication, SEST11 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi

Organism-specific databases

EuPathDBiHostDB:ENSG00000080546.13
HGNCiHGNC:21595 SESN1
MIMi606103 gene
neXtProtiNX_Q9Y6P5

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, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi130C → S: Loss of the ability to decrease intracellular reactive oxygen species. 1 Publication1

Organism-specific databases

DisGeNETi27244
OpenTargetsiENSG00000080546
PharmGKBiPA134927596

Polymorphism and mutation databases

BioMutaiSESN1
DMDMi13633953

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002211781 – 492Sestrin-1Add BLAST492

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei293PhosphoserineCombined sources1
Modified residuei314PhosphoserineCombined sources1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ9Y6P5
PaxDbiQ9Y6P5
PeptideAtlasiQ9Y6P5
PRIDEiQ9Y6P5

PTM databases

iPTMnetiQ9Y6P5
PhosphoSitePlusiQ9Y6P5

Expressioni

Tissue specificityi

Widely expressed.1 Publication

Inductioni

Isoform T2 and isoform T3 are induced by genotoxic stress (UV, gamma-irradiation and cytotoxic drugs) in a p53/TP53-dependent manner. Isoform T1 is not induced by p53/TP53.1 Publication

Gene expression databases

BgeeiENSG00000080546
CleanExiHS_SESN1
GenevisibleiQ9Y6P5 HS

Organism-specific databases

HPAiHPA073659

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:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). Interacts with KEAP1, RBX1 and SQSTM1; in the SQSTM1-dependent autophagic degradation of KEAP1 (PubMed:23274085). May interact with PRDX1 (PubMed:15105503).5 Publications

Protein-protein interaction databases

BioGridi118092, 5 interactors
DIPiDIP-62046N
IntActiQ9Y6P5, 6 interactors
STRINGi9606.ENSP00000393762

Structurei

3D structure databases

ProteinModelPortaliQ9Y6P5
SMRiQ9Y6P5
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni71 – 252N-terminal domain; mediates the alkylhydroperoxide reductase activityBy similarityAdd BLAST182
Regioni321 – 492C-terminal domain; mediates TORC1 regulationBy similarityAdd BLAST172
Regioni386 – 389Leucine-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
InParanoidiQ9Y6P5
KOiK10141
OMAiRQFQHSE
OrthoDBiEOG091G0IVA
PhylomeDBiQ9Y6P5
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

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform T2 (identifier: Q9Y6P5-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MRLAAAANEA YTAPLAVSGL LGCKQCGGGR DQDEELGIRI PRPLGQGPSR
60 70 80 90 100
FIPEKEILQV GSEDAQMHAL FADSFAALGR LDNITLVMVF HPQYLESFLK
110 120 130 140 150
TQHYLLQMDG PLPLHYRHYI GIMAAARHQC SYLVNLHVND FLHVGGDPKW
160 170 180 190 200
LNGLENAPQK LQNLGELNKV LAHRPWLITK EHIEGLLKAE EHSWSLAELV
210 220 230 240 250
HAVVLLTHYH SLASFTFGCG ISPEIHCDGG HTFRPPSVSN YCICDITNGN
260 270 280 290 300
HSVDEMPVNS AENVSVSDSF FEVEALMEKM RQLQECRDEE EASQEEMASR
310 320 330 340 350
FEIEKRESMF VFSSDDEEVT PARAVSRHFE DTSYGYKDFS RHGMHVPTFR
360 370 380 390 400
VQDYCWEDHG YSLVNRLYPD VGQLIDEKFH IAYNLTYNTM AMHKDVDTSM
410 420 430 440 450
LRRAIWNYIH CMFGIRYDDY DYGEINQLLD RSFKVYIKTV VCTPEKVTKR
460 470 480 490
MYDSFWRQFK HSEKVHVNLL LIEARMQAEL LYALRAITRY MT
Length:492
Mass (Da):56,557
Last modified:April 27, 2001 - v2
Checksum:i824CF6513634C35E
GO
Isoform T1 (identifier: Q9Y6P5-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-34: MRLAAAANEAYTAPLAVSGLLGCKQCGGGRDQDE → MAEGENEVRW...KSEFILKSIQ

Show »
Length:551
Mass (Da):63,826
Checksum:iABFE480007D623BE
GO
Isoform T3 (identifier: Q9Y6P5-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-66: Missing.

Show »
Length:426
Mass (Da):49,624
Checksum:i7B076B9C7783E125
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01421044L → I1 PublicationCorresponds to variant dbSNP:rs2273668Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0060601 – 66Missing in isoform T3. 1 PublicationAdd BLAST66
Alternative sequenceiVSP_0060591 – 34MRLAA…RDQDE → MAEGENEVRWDGLCSRDSTT RETALENIRQTILRKTEYLR SVKETPHRPSDGLSNTESSD GLNKLLAHLLMLSKRCPFKD VREKSEFILKSIQ in isoform T1. 2 PublicationsAdd BLAST34

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF033122 mRNA Translation: AAD04812.1
AF033120 mRNA Translation: AAD04810.1
AF033121 mRNA Translation: AAD04811.1
AL390208 Genomic DNA No translation available.
CH471051 Genomic DNA Translation: EAW48367.1
CH471051 Genomic DNA Translation: EAW48368.1
BC112036 mRNA Translation: AAI12037.1
BC113569 mRNA Translation: AAI13570.1
AK001886 mRNA Translation: BAA91961.1
CCDSiCCDS5070.1 [Q9Y6P5-2]
CCDS56444.1 [Q9Y6P5-3]
CCDS56445.1 [Q9Y6P5-1]
RefSeqiNP_001186862.1, NM_001199933.1 [Q9Y6P5-1]
NP_001186863.1, NM_001199934.1 [Q9Y6P5-3]
NP_055269.1, NM_014454.2 [Q9Y6P5-2]
UniGeneiHs.591336

Genome annotation databases

EnsembliENST00000302071; ENSP00000306734; ENSG00000080546 [Q9Y6P5-3]
ENST00000356644; ENSP00000349061; ENSG00000080546 [Q9Y6P5-1]
ENST00000436639; ENSP00000393762; ENSG00000080546 [Q9Y6P5-2]
GeneIDi27244
KEGGihsa:27244
UCSCiuc003pst.5 human [Q9Y6P5-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Entry informationi

Entry nameiSESN1_HUMAN
AccessioniPrimary (citable) accession number: Q9Y6P5
Secondary accession number(s): Q2M2B7
, Q5T316, Q9NV00, Q9UPD5, Q9Y6P6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: April 27, 2001
Last modified: May 23, 2018
This is version 143 of the entry and version 2 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

Complete proteome, Reference proteome

Documents

  1. Human chromosome 6
    Human chromosome 6: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

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