SESN2_BOVIN
ID SESN2_BOVIN Reviewed; 471 AA.
AC Q58CN8; Q08E69;
DT 04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 2.
DT 03-AUG-2022, entry version 102.
DE RecName: Full=Sestrin-2 {ECO:0000305};
DE EC=1.11.1.- {ECO:0000250|UniProtKB:P58004};
GN Name=SESN2 {ECO:0000250|UniProtKB:P58004};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=16305752; DOI=10.1186/1471-2164-6-166;
RA Harhay G.P., Sonstegard T.S., Keele J.W., Heaton M.P., Clawson M.L.,
RA Snelling W.M., Wiedmann R.T., Van Tassell C.P., Smith T.P.L.;
RT "Characterization of 954 bovine full-CDS cDNA sequences.";
RL BMC Genomics 6:166-166(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=Hereford; TISSUE=Hypothalamus;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
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. This
CC stress-inducible metabolic regulator also plays a role in protection
CC against oxidative and genotoxic stresses. May negatively regulate
CC protein translation in response to endoplasmic reticulum stress, via
CC TORC1. May positively regulate the transcription by NFE2L2 of genes
CC involved in the response to oxidative stress by facilitating the
CC SQSTM1-mediated autophagic degradation of KEAP1. May also mediate TP53
CC inhibition of TORC1 signaling upon genotoxic stress. Moreover, may
CC prevent the accumulation of reactive oxygen species (ROS) through the
CC alkylhydroperoxide reductase activity born by the N-terminal domain of
CC the protein. Was originally reported to contribute to oxidative stress
CC resistance by reducing PRDX1. However, this could not be confirmed.
CC {ECO:0000250|UniProtKB:P58004}.
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. Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function
CC as a guanine nucleotide dissociation inhibitor for RRAGs and regulate
CC them. May interact with the TORC2 complex. Interacts with KEAP1, RBX1,
CC SQSTM and ULK1; to regulate the degradation of KEAP1. May also
CC associate with the complex composed of TSC1, TSC2 and the AMP-
CC responsive protein kinase/AMPK to regulate TORC1 signaling. May
CC interact with PRDX1. {ECO:0000250|UniProtKB:P58004}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P58004}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q58CN8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q58CN8-2; Sequence=VSP_025032;
CC -!- DOMAIN: The N-terminal domain has 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 -!- PTM: Phosphorylated by ULK1 at multiple sites.
CC {ECO:0000250|UniProtKB:P58004}.
CC -!- PTM: Ubiquitinated at Lys-166 by RNF167 via 'Lys-63'-linked
CC polyubiquitination in response to leucine deprivation: ubiquitination
CC promotes SESN2-interaction with the GATOR2 complex, leading to inhibit
CC the TORC1 signaling pathway. Deubiquitinated at Lys-166 by STAMBPL1,
CC promoting the TORC1 signaling pathway. Ubiquitinated by RNF186;
CC ubiquitination mediates proteasomal degradation.
CC {ECO:0000250|UniProtKB:P58004}.
CC -!- SIMILARITY: Belongs to the sestrin family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; BT021909; AAX46756.1; -; mRNA.
DR EMBL; BC123386; AAI23387.1; -; mRNA.
DR RefSeq; NP_001019678.1; NM_001024507.1.
DR RefSeq; XP_005203155.1; XM_005203098.2. [Q58CN8-1]
DR AlphaFoldDB; Q58CN8; -.
DR SMR; Q58CN8; -.
DR STRING; 9913.ENSBTAP00000055856; -.
DR PaxDb; Q58CN8; -.
DR PRIDE; Q58CN8; -.
DR Ensembl; ENSBTAT00000042886; ENSBTAP00000040490; ENSBTAG00000002363. [Q58CN8-1]
DR GeneID; 509863; -.
DR KEGG; bta:509863; -.
DR CTD; 83667; -.
DR VEuPathDB; HostDB:ENSBTAG00000002363; -.
DR eggNOG; KOG3746; Eukaryota.
DR GeneTree; ENSGT00950000183168; -.
DR HOGENOM; CLU_020429_0_0_1; -.
DR InParanoid; Q58CN8; -.
DR OMA; GSHMTEF; -.
DR OrthoDB; 588598at2759; -.
DR TreeFam; TF314230; -.
DR Reactome; R-BTA-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-BTA-9755511; KEAP1-NFE2L2 pathway.
DR Proteomes; UP000009136; Chromosome 2.
DR Bgee; ENSBTAG00000002363; Expressed in esophagus and 103 other tissues.
DR GO; GO:1990316; C:Atg1/ULK1 kinase complex; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:InterPro.
DR GO; GO:0070728; F:leucine binding; ISS:UniProtKB.
DR GO; GO:0016684; F:oxidoreductase activity, acting on peroxide as acceptor; ISS:UniProtKB.
DR GO; GO:0140311; F:protein sequestering activity; ISS:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISS:UniProtKB.
DR GO; GO:0032542; F:sulfiredoxin activity; IEA:Ensembl.
DR GO; GO:0098869; P:cellular oxidant detoxification; ISS:UniProtKB.
DR GO; GO:0042149; P:cellular response to glucose starvation; IEA:Ensembl.
DR GO; GO:0071233; P:cellular response to leucine; IBA:GO_Central.
DR GO; GO:1990253; P:cellular response to leucine starvation; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; ISS:UniProtKB.
DR GO; GO:1904262; P:negative regulation of TORC1 signaling; ISS:UniProtKB.
DR GO; GO:1902010; P:negative regulation of translation in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; ISS:UniProtKB.
DR GO; GO:1900182; P:positive regulation of protein localization to nucleus; ISS:UniProtKB.
DR GO; GO:0036091; P:positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; ISS:UniProtKB.
DR GO; GO:0001932; P:regulation of protein phosphorylation; ISS:UniProtKB.
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 2: Evidence at transcript level;
KW Acetylation; Alternative splicing; Cytoplasm; Isopeptide bond;
KW Oxidoreductase; Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1..471
FT /note="Sestrin-2"
FT /id="PRO_0000231009"
FT REGION 57..230
FT /note="N-terminal domain; mediates the alkylhydroperoxide
FT reductase activity"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT REGION 212..241
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 299..471
FT /note="C-terminal domain; mediates TORC1 regulation"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT COMPBIAS 215..229
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 116
FT /note="Cysteine sulfenic acid (-SOH) intermediate"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 365..368
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 377
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 442
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT MOD_RES 240
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT CROSSLNK 166
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT VAR_SEQ 445..471
FT /note="HVNLLLLEARMQAALLYALRAITRYMT -> RLVGEEQDGSLRRRRGLGTQR
FT GPDLGIHPASLHVSCIGRQILYHERPLGSPFTHL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16305752"
FT /id="VSP_025032"
FT CONFLICT 331
FT /note="Q -> R (in Ref. 1; AAX46756)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 471 AA; 53600 MW; A40CAA20C594F349 CRC64;
MIVADSECRA ELKGYLPGAG EEQRESRVRR GPRGPSAFIP VEEVLQEGAE SLEQHLGLEA
LMSSGRVDNL AVVMGLHPDY FTSFWRLHCL LLHTDGPLAN SWRHYIAIMA AARHQCSYLV
GSHMAEFLQT GGDPEWLLGL HRAPEKLRKL SEINKLLAHR PWLITKEHIQ ALLKTGEHSW
SLAELIQALV LLTHCHSLAS FVFGCGILPE GDPEGSPAPQ APSPPSEQST PPSRDSLNHS
GGFEAARDVE ALMERMRQLQ ESLLQDEGAS QEEMESRFEL EKSESLLVTP SVDILEPFAN
PDMLCFVEDP TFGYEDFTRR GTQAPPTFRA QDYTWEDHGY SLIQRLYPEG GQLLDEKFQA
AYSLTYNTIA MHSGVDTSVL RRAIWNYIHC VFGIRYDDYD YGEVNQLLER NLKVYIKTVA
CYPEKTTRRM YNHFWRHFRH SEKVHVNLLL LEARMQAALL YALRAITRYM T
