SESN2_PONAB
ID SESN2_PONAB Reviewed; 480 AA.
AC Q5RCB4;
DT 12-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 62.
DE RecName: Full=Sestrin-2 {ECO:0000305};
DE EC=1.11.1.- {ECO:0000250|UniProtKB:P58004};
GN Name=SESN2 {ECO:0000250|UniProtKB:P58004};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) 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 -!- 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-175 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-175 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}.
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DR EMBL; CR858363; CAH90593.1; -; mRNA.
DR RefSeq; NP_001125320.1; NM_001131848.1.
DR AlphaFoldDB; Q5RCB4; -.
DR SMR; Q5RCB4; -.
DR STRING; 9601.ENSPPYP00000001899; -.
DR GeneID; 100172219; -.
DR KEGG; pon:100172219; -.
DR CTD; 83667; -.
DR eggNOG; KOG3746; Eukaryota.
DR InParanoid; Q5RCB4; -.
DR OrthoDB; 588598at2759; -.
DR Proteomes; UP000001595; Unplaced.
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:0098869; P:cellular oxidant detoxification; ISS:UniProtKB.
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; Cytoplasm; Isopeptide bond; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1..480
FT /note="Sestrin-2"
FT /id="PRO_0000290025"
FT REGION 20..45
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 66..239
FT /note="N-terminal domain; mediates the alkylhydroperoxide
FT reductase activity"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT REGION 222..252
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 308..480
FT /note="C-terminal domain; mediates TORC1 regulation"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT ACT_SITE 125
FT /note="Cysteine sulfenic acid (-SOH) intermediate"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 374..377
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 386
FT /ligand="L-leucine"
FT /ligand_id="ChEBI:CHEBI:57427"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT BINDING 451
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 249
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P58004"
FT CROSSLNK 175
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P58004"
SQ SEQUENCE 480 AA; 54452 MW; 38990A9ED8A38C90 CRC64;
MIVADSECRA ELKDYLRFAP GGVGDSGPGE EQRESRARRG PRGPSAFIPV EEVLREGAES
LEQHLGLEAL MSSGRVDNLA VVMGLHPDYF TSFWRLHYLP LHTDGPLASS WRHYIAIMAA
ARHQCSYLVG SHMAEFLQTG GDPEWLLGLH RAPEKLRKLS EINKLLAHRP WLITKEHIQA
LLKTGEHTWS LAELIQALVL LTHCHSLSSF VFGCGILPEG DADGSPAPQA PTPPSEQSSP
PSRDPLNNSG GFESARDVEA LMERMRQLQE SLLRDEGTSQ EEMESRFELE KSESLLVTPS
ADILEPSPHP DMLCFVEDPA FGYEDFTRRG AQAPPTFRAQ DYTWEDHGYS LIQRLYPEGG
QLLDEKFQAA YSLTYNTIAM LSGVDTSVLR RAIWNYIHCV FGIRYDDYDY GEVNQLLERN
LKVYIKTVAC YPEKTTRRMY NLFWRHFRHS EKVHVNLLLL EARMQAALLY ALRAITRYMT