SESN1_MOUSE
ID SESN1_MOUSE Reviewed; 492 AA.
AC P58006; E9QPK0; Q7TNF3;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=Sestrin-1 {ECO:0000305};
DE EC=1.11.1.- {ECO:0000250|UniProtKB:P58004};
GN Name=Sesn1 {ECO:0000312|MGI:MGI:2155278};
GN Synonyms=Pa26 {ECO:0000303|PubMed:12607115},
GN Sest1 {ECO:0000303|PubMed:12607115};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP RECONSTRUCTION FROM ESTS.
RX PubMed=12607115; DOI=10.1007/s00439-003-0917-5;
RA Peeters H., Debeer P., Bairoch A., Wilquet V., Huysmans C., Parthoens E.,
RA Fryns J.-P., Gewillig M., Nakamura Y., Niikawa N., Van De Ven W.,
RA Devriendt K.;
RT "PA26 is a candidate gene for heterotaxia in humans: identification of a
RT novel PA26-related gene family in human and mouse.";
RL Hum. Genet. 112:573-580(2003).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, INTERACTION WITH RRAGA; RRAGB; RRAGC AND RRAGD, TISSUE
RP SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=25259925; DOI=10.1016/j.cell.2014.08.038;
RA Peng M., Yin N., Li M.O.;
RT "Sestrins function as guanine nucleotide dissociation inhibitors for Rag
RT GTPases to control mTORC1 signaling.";
RL Cell 159:122-133(2014).
CC -!- FUNCTION: Functions as an intracellular leucine sensor that negatively
CC regulates the TORC1 signaling pathway through the GATOR complex. In
CC absence of leucine, binds the GATOR subcomplex GATOR2 and prevents
CC TORC1 signaling. Binding of leucine to SESN2 disrupts its interaction
CC with GATOR2 thereby activating the TORC1 signaling pathway
CC (PubMed:25259925). This stress-inducible metabolic regulator may also
CC play a role in protection against oxidative and genotoxic stresses. May
CC positively regulate the transcription by NFE2L2 of genes involved in
CC the response to oxidative stress by facilitating the SQSTM1-mediated
CC autophagic degradation of KEAP1. Moreover, may prevent the accumulation
CC of reactive oxygen species (ROS) through the alkylhydroperoxide
CC reductase activity born by the N-terminal domain of the protein. Was
CC originally reported to contribute to oxidative stress resistance by
CC reducing PRDX1. However, this could not be confirmed (By similarity).
CC {ECO:0000250|UniProtKB:P58004, ECO:0000269|PubMed:25259925}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a hydroperoxide + L-cysteinyl-[protein] = an alcohol + S-
CC hydroxy-L-cysteinyl-[protein]; Xref=Rhea:RHEA:67124, Rhea:RHEA-
CC COMP:10131, Rhea:RHEA-COMP:17193, ChEBI:CHEBI:29950,
CC ChEBI:CHEBI:30879, ChEBI:CHEBI:35924, ChEBI:CHEBI:61973;
CC Evidence={ECO:0000250|UniProtKB:P58004};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67125;
CC Evidence={ECO:0000250|UniProtKB:P58004};
CC -!- SUBUNIT: Interacts with the GATOR2 complex which is composed of MIOS,
CC SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated
CC by leucine (By similarity). Interacts with RRAGA, RRAGB, RRAGC and
CC RRAGD; may function as a guanine nucleotide dissociation inhibitor for
CC RRAGs and regulate them (PubMed:25259925). Interacts with KEAP1, RBX1
CC and SQSTM1; in the SQSTM1-dependent autophagic degradation of KEAP1.
CC May interact with PRDX1 (By similarity). {ECO:0000250|UniProtKB:Q9Y6P5,
CC ECO:0000269|PubMed:25259925}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9Y6P5}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9Y6P5}.
CC -!- TISSUE SPECIFICITY: Highly expressed in heart and also detected in
CC liver and skeletal muscles (at protein level).
CC {ECO:0000269|PubMed:25259925}.
CC -!- DOMAIN: The N-terminal domain may have an alkylhydroperoxide reductase
CC activity. {ECO:0000250|UniProtKB:P58004}.
CC -!- DOMAIN: The C-terminal domain mediates interaction with GATOR2 through
CC which it regulates TORC1 signaling. {ECO:0000250|UniProtKB:P58004}.
CC -!- DISRUPTION PHENOTYPE: Triple knockout mice lacking Sesn1, Sesn2 and
CC Sesn3 do not display an embryonic lethal phenotype since they are born
CC at an expected Mendelian ratio. Moreover, they are not distinguishable
CC from their wild-type littermates. However, their survival at 10 days is
CC dramatically affected. This is associated with a constitutive
CC activation of TORC1 signaling in the liver, heart and skeletal muscle
CC during postnatal fasting, that occurs between birth and suckling.
CC {ECO:0000269|PubMed:25259925}.
CC -!- SIMILARITY: Belongs to the sestrin family. {ECO:0000305}.
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DR EMBL; AC115297; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC165442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC055753; AAH55753.1; -; mRNA.
DR CCDS; CCDS23809.1; -.
DR RefSeq; NP_001013388.2; NM_001013370.2.
DR AlphaFoldDB; P58006; -.
DR SMR; P58006; -.
DR STRING; 10090.ENSMUSP00000097515; -.
DR iPTMnet; P58006; -.
DR PhosphoSitePlus; P58006; -.
DR EPD; P58006; -.
DR MaxQB; P58006; -.
DR PaxDb; P58006; -.
DR PRIDE; P58006; -.
DR ProteomicsDB; 256624; -.
DR Antibodypedia; 32228; 276 antibodies from 31 providers.
DR DNASU; 140742; -.
DR Ensembl; ENSMUST00000041438; ENSMUSP00000043034; ENSMUSG00000038332.
DR GeneID; 140742; -.
DR KEGG; mmu:140742; -.
DR UCSC; uc007eyf.2; mouse.
DR CTD; 27244; -.
DR MGI; MGI:2155278; Sesn1.
DR VEuPathDB; HostDB:ENSMUSG00000038332; -.
DR eggNOG; KOG3746; Eukaryota.
DR GeneTree; ENSGT00950000183168; -.
DR HOGENOM; CLU_020429_2_0_1; -.
DR InParanoid; P58006; -.
DR OMA; CIFGIRH; -.
DR Reactome; R-MMU-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-MMU-9639288; Amino acids regulate mTORC1.
DR Reactome; R-MMU-9755511; KEAP1-NFE2L2 pathway.
DR BioGRID-ORCS; 140742; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Sesn1; mouse.
DR PRO; PR:P58006; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; P58006; protein.
DR Bgee; ENSMUSG00000038332; Expressed in myocardium of ventricle and 252 other tissues.
DR ExpressionAtlas; P58006; baseline and differential.
DR Genevisible; P58006; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0001650; C:fibrillar center; ISO:MGI.
DR GO; GO:0061700; C:GATOR2 complex; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0070728; F:leucine binding; ISS:UniProtKB.
DR GO; GO:0016684; F:oxidoreductase activity, acting on peroxide as acceptor; IBA:GO_Central.
DR GO; GO:0098869; P:cellular oxidant detoxification; ISS:UniProtKB.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IMP:UniProtKB.
DR GO; GO:0042149; P:cellular response to glucose starvation; ISO:MGI.
DR GO; GO:0071233; P:cellular response to leucine; IBA:GO_Central.
DR GO; GO:1990253; P:cellular response to leucine starvation; IBA:GO_Central.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IMP:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IBA:GO_Central.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; ISS:UniProtKB.
DR GO; GO:0051896; P:regulation of protein kinase B signaling; IDA:MGI.
DR GO; GO:1901031; P:regulation of response to reactive oxygen species; IEA:InterPro.
DR Gene3D; 1.20.1290.10; -; 1.
DR InterPro; IPR029032; AhpD-like.
DR InterPro; IPR006730; Sestrin.
DR PANTHER; PTHR12474; PTHR12474; 1.
DR Pfam; PF04636; PA26; 1.
DR SUPFAM; SSF69118; SSF69118; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Nucleus; Oxidoreductase; Phosphoprotein; Reference proteome.
FT CHAIN 1..492
FT /note="Sestrin-1"
FT /id="PRO_0000221179"
FT REGION 71..252
FT /note="N-terminal domain; may mediate the
FT alkylhydroperoxide reductase activity"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT REGION 321..492
FT /note="C-terminal domain; mediates TORC1 regulation"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT ACT_SITE 130
FT /note="Cysteine sulfenic acid (-SOH) intermediate"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 386..389
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 398
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 463
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT MOD_RES 293
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6P5"
FT MOD_RES 314
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6P5"
FT CONFLICT 382
FT /note="A -> P (in Ref. 2; AAH55753)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 492 AA; 56637 MW; 1DF5CF63A45F52F2 CRC64;
MRLAAASNEA YAASLAVSEL LSCHQCGGDR GQDEELGIRI PRPLGHGPSR FIPEKEMLQV
GSEDAQMHAL FADSFAALGR LDNITLVMVF HPQYLESFLK TQHYLLQMDG PLPLHYRHYI
GIMAAARHQC SYLVNLHVSD FLHVGGDPKW LNGLENAPQK LQNLGELNKV LAHRPWLITK
EHIEGLLKAE EHSWSLAELV HAVVLLTHYH SLASFTFGCG ISPEIHCDGG HTFRPPSVSN
YCICDITNGN HSVDEMQVNS AGNASVSDSF FEVEALMEKM RQLQECREEE EASQEEMASR
FEMEKRESMF VFSSDDDEVT PARDVSRHFE DTSYGYKDFS RHGMHVPTFR VQDYCWEDHG
YSLVNRLYPD VGQLIDEKFH IAYNLTYNTM AMHKDVDTSM LRRAIWNYIH CMFGIRYDDY
DYGEINQLLD RSFKVYIKTV VCTPEKVTKR MYDSFWRQFK HSEKVHVNLL LIEARMQAEL
LYALRAITRY MT
