SESN3_HUMAN
ID SESN3_HUMAN Reviewed; 492 AA.
AC P58005; B7Z7P9; Q96AD1;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2002, sequence version 2.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Sestrin-3 {ECO:0000305};
DE EC=1.11.1.- {ECO:0000250|UniProtKB:P58004};
GN Name=SESN3 {ECO:0000312|HGNC:HGNC:23060};
GN Synonyms=SEST3 {ECO:0000303|PubMed:12607115};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Lung;
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 [4]
RP IDENTIFICATION, AND TISSUE SPECIFICITY.
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 [5]
RP INTERACTION WITH RRAGA; RRAGB; RRAGC AND RRAGD.
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).
RN [6]
RP FUNCTION, INTERACTION WITH GATOR2 COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=25263562; DOI=10.1016/j.celrep.2014.09.014;
RA Chantranupong L., Wolfson R.L., Orozco J.M., Saxton R.A., Scaria S.M.,
RA Bar-Peled L., Spooner E., Isasa M., Gygi S.P., Sabatini D.M.;
RT "The Sestrins interact with GATOR2 to negatively regulate the amino-acid-
RT sensing pathway upstream of mTORC1.";
RL Cell Rep. 9:1-8(2014).
RN [7]
RP INTERACTION WITH GATOR2 COMPLEX.
RX PubMed=26449471; DOI=10.1126/science.aab2674;
RA Wolfson R.L., Chantranupong L., Saxton R.A., Shen K., Scaria S.M.,
RA Cantor J.R., Sabatini D.M.;
RT "Sestrin2 is a leucine sensor for the mTORC1 pathway.";
RL Science 351:43-48(2016).
CC -!- FUNCTION: May function as an intracellular leucine sensor that
CC negatively regulates the TORC1 signaling pathway (PubMed:25263562). May
CC also regulate the insulin-receptor signaling pathway through activation
CC of TORC2 (By similarity). This metabolic regulator may also play a role
CC in protection against oxidative and genotoxic stresses (By similarity).
CC May prevent the accumulation of reactive oxygen species (ROS) through
CC the alkylhydroperoxide reductase activity born by the N-terminal domain
CC of the protein (By similarity). {ECO:0000250|UniProtKB:P58004,
CC ECO:0000250|UniProtKB:Q9CYP7, ECO:0000269|PubMed:25263562}.
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 not regulated by
CC leucine (PubMed:25263562, PubMed:26449471). Interacts with RRAGA,
CC RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide
CC dissociation inhibitor for RRAGs and regulate them (PubMed:25259925).
CC Interacts with the TORC2 complex; through RICTOR (By similarity).
CC {ECO:0000250|UniProtKB:Q9CYP7, ECO:0000269|PubMed:25259925,
CC ECO:0000269|PubMed:25263562, ECO:0000269|PubMed:26449471}.
CC -!- INTERACTION:
CC P58005; Q96S15: WDR24; NbExp=3; IntAct=EBI-16179942, EBI-746424;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:25263562}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P58005-1; Sequence=Displayed;
CC Name=3;
CC IsoId=P58005-3; Sequence=VSP_006063, VSP_006064;
CC Name=2;
CC IsoId=P58005-4; Sequence=VSP_054563, VSP_054564;
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:12607115}.
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 -!- SIMILARITY: Belongs to the sestrin family. {ECO:0000305}.
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DR EMBL; AK096300; BAC04754.1; -; mRNA.
DR EMBL; AK302366; BAH13685.1; -; mRNA.
DR EMBL; AP000787; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC017296; AAH17296.1; -; mRNA.
DR CCDS; CCDS60938.1; -. [P58005-4]
DR CCDS; CCDS8303.1; -. [P58005-1]
DR RefSeq; NP_001258523.1; NM_001271594.1. [P58005-4]
DR RefSeq; NP_653266.2; NM_144665.3. [P58005-1]
DR AlphaFoldDB; P58005; -.
DR SMR; P58005; -.
DR BioGRID; 126817; 14.
DR DIP; DIP-62045N; -.
DR IntAct; P58005; 5.
DR STRING; 9606.ENSP00000441927; -.
DR iPTMnet; P58005; -.
DR PhosphoSitePlus; P58005; -.
DR BioMuta; SESN3; -.
DR DMDM; 20141774; -.
DR EPD; P58005; -.
DR jPOST; P58005; -.
DR MassIVE; P58005; -.
DR MaxQB; P58005; -.
DR PaxDb; P58005; -.
DR PeptideAtlas; P58005; -.
DR PRIDE; P58005; -.
DR ProteomicsDB; 57044; -. [P58005-1]
DR ProteomicsDB; 57046; -. [P58005-3]
DR Antibodypedia; 31660; 224 antibodies from 30 providers.
DR DNASU; 143686; -.
DR Ensembl; ENST00000278499.6; ENSP00000278499.2; ENSG00000149212.12. [P58005-4]
DR Ensembl; ENST00000416495.6; ENSP00000407008.2; ENSG00000149212.12. [P58005-3]
DR Ensembl; ENST00000536441.7; ENSP00000441927.1; ENSG00000149212.12. [P58005-1]
DR GeneID; 143686; -.
DR KEGG; hsa:143686; -.
DR MANE-Select; ENST00000536441.7; ENSP00000441927.1; NM_144665.4; NP_653266.2.
DR UCSC; uc001pfj.5; human. [P58005-1]
DR CTD; 143686; -.
DR DisGeNET; 143686; -.
DR GeneCards; SESN3; -.
DR HGNC; HGNC:23060; SESN3.
DR HPA; ENSG00000149212; Low tissue specificity.
DR MIM; 607768; gene.
DR neXtProt; NX_P58005; -.
DR OpenTargets; ENSG00000149212; -.
DR PharmGKB; PA134914983; -.
DR VEuPathDB; HostDB:ENSG00000149212; -.
DR eggNOG; KOG3746; Eukaryota.
DR GeneTree; ENSGT00950000183168; -.
DR HOGENOM; CLU_020429_2_0_1; -.
DR InParanoid; P58005; -.
DR OMA; NSLNERM; -.
DR OrthoDB; 588598at2759; -.
DR PhylomeDB; P58005; -.
DR TreeFam; TF314230; -.
DR PathwayCommons; P58005; -.
DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes.
DR SignaLink; P58005; -.
DR SIGNOR; P58005; -.
DR BioGRID-ORCS; 143686; 11 hits in 1084 CRISPR screens.
DR ChiTaRS; SESN3; human.
DR GenomeRNAi; 143686; -.
DR Pharos; P58005; Tbio.
DR PRO; PR:P58005; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P58005; protein.
DR Bgee; ENSG00000149212; Expressed in sperm and 191 other tissues.
DR ExpressionAtlas; P58005; baseline and differential.
DR Genevisible; P58005; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:InterPro.
DR GO; GO:0031932; C:TORC2 complex; IEA:Ensembl.
DR GO; GO:0070728; F:leucine binding; IBA:GO_Central.
DR GO; GO:0016684; F:oxidoreductase activity, acting on peroxide as acceptor; IBA:GO_Central.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB.
DR GO; GO:0042149; P:cellular response to glucose starvation; IMP:UniProtKB.
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:0042593; P:glucose homeostasis; IEA:Ensembl.
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:0046626; P:regulation of insulin receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0051896; P:regulation of protein kinase B signaling; IEA:Ensembl.
DR GO; GO:1901031; P:regulation of response to reactive oxygen species; IEA:InterPro.
DR GO; GO:0032868; P:response to insulin; IEA:Ensembl.
DR GO; GO:0038203; P:TORC2 signaling; IEA:Ensembl.
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 Alternative splicing; Cytoplasm; Oxidoreductase; Reference proteome.
FT CHAIN 1..492
FT /note="Sestrin-3"
FT /id="PRO_0000221183"
FT REGION 62..243
FT /note="N-terminal domain; may mediate the
FT alkylhydroperoxide reductase activity"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT REGION 310..492
FT /note="C-terminal domain; mediates TORC1 regulation"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT ACT_SITE 121
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 VAR_SEQ 1..78
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054563"
FT VAR_SEQ 115..175
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054564"
FT VAR_SEQ 313..321
FT /note="DFEDDMIIT -> GAFLHFFAF (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_006063"
FT VAR_SEQ 322..492
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_006064"
FT VARIANT 71
FT /note="R -> C (in dbSNP:rs10160385)"
FT /id="VAR_051958"
FT VARIANT 227
FT /note="I -> T (in dbSNP:rs11021069)"
FT /id="VAR_051959"
SQ SEQUENCE 492 AA; 57291 MW; 0B165C6BAE5A49CF CRC64;
MNRGGGSPSA AANYLLCTNC RKVLRKDKRI RVSQPLTRGP SAFIPEKEVV QANTVDERTN
FLVEEYSTSG RLDNITQVMS LHTQYLESFL RSQFYMLRMD GPLPLPYRHY IAIMAAARHQ
CSYLINMHVD EFLKTGGIAE WLNGLEYVPQ RLKNLNEINK LLAHRPWLIT KEHIQKLVKT
GENNWSLPEL VHAVVLLAHY HALASFVFGS GINPERDPEI SNGFRLISVN NFCVCDLAND
NNIENASLSG SNFGIVDSLS ELEALMERMK RLQEEREDEE ASQEEMSTRF EKEKKESLFV
VSGDTFHSFP HSDFEDDMII TSDVSRYIED PGFGYEDFAR RGEEHLPTFR AQDYTWENHG
FSLVNRLYSD IGHLLDEKFR MVYNLTYNTM ATHEDVDTTM LRRALFNYVH CMFGIRYDDY
DYGEVNQLLE RSLKVYIKTV TCYPERTTKR MYDSYWRQFK HSEKVHVNLL LMEARMQAEL
LYALRAITRH LT
