SIR2_CAEEL
ID SIR2_CAEEL Reviewed; 607 AA.
AC Q21921;
DT 19-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 145.
DE RecName: Full=NAD-dependent protein deacetylase sir-2.1;
DE EC=2.3.1.286;
DE AltName: Full=Protein sir-2.1;
DE AltName: Full=Regulatory protein SIR2 homolog 1;
GN Name=sir-2.1 {ECO:0000312|WormBase:R11A8.4a};
GN ORFNames=R11A8.4 {ECO:0000312|WormBase:R11A8.4a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2;
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2]
RP FUNCTION.
RX PubMed=11242085; DOI=10.1038/35065638;
RA Tissenbaum H.A., Guarente L.;
RT "Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis
RT elegans.";
RL Nature 410:227-230(2001).
RN [3]
RP FUNCTION.
RX PubMed=16256736; DOI=10.1016/j.devcel.2005.09.017;
RA Viswanathan M., Kim S.K., Berdichevsky A., Guarente L.;
RT "A role for SIR-2.1 regulation of ER stress response genes in determining
RT C. elegans life span.";
RL Dev. Cell 9:605-615(2005).
RN [4]
RP FUNCTION.
RX PubMed=15793589; DOI=10.1038/ng1534;
RA Parker J.A., Arango M., Abderrahmane S., Lambert E., Tourette C.,
RA Catoire H., Neri C.;
RT "Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and
RT mammalian neurons.";
RL Nat. Genet. 37:349-350(2005).
RN [5]
RP FUNCTION, INTERACTION WITH DAF-16; FTT-2 AND PAR-5, AND SUBCELLULAR
RP LOCATION.
RX PubMed=16777605; DOI=10.1016/j.cell.2006.04.036;
RA Berdichevsky A., Viswanathan M., Horvitz H.R., Guarente L.;
RT "C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and
RT extend life span.";
RL Cell 125:1165-1177(2006).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX PubMed=16280150; DOI=10.1016/j.mad.2005.09.005;
RA Wang Y., Tissenbaum H.A.;
RT "Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and
RT DAF-16/FOXO.";
RL Mech. Ageing Dev. 127:48-56(2006).
RN [7] {ECO:0000305}
RP FUNCTION, AND INTERACTION WITH HCF-1.
RX PubMed=21909281; DOI=10.1371/journal.pgen.1002235;
RA Rizki G., Iwata T.N., Li J., Riedel C.G., Picard C.L., Jan M., Murphy C.T.,
RA Lee S.S.;
RT "The evolutionarily conserved longevity determinants HCF-1 and SIR-
RT 2.1/SIRT1 collaborate to regulate DAF-16/FOXO.";
RL PLoS Genet. 7:E1002235-E1002235(2011).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22393255; DOI=10.1128/mcb.06546-11;
RA Wells M.B., Snyder M.J., Custer L.M., Csankovszki G.;
RT "Caenorhabditis elegans dosage compensation regulates histone H4 chromatin
RT state on X chromosomes.";
RL Mol. Cell. Biol. 32:1710-1719(2012).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24077178; DOI=10.1038/nchembio.1352;
RA Schmeisser K., Mansfeld J., Kuhlow D., Weimer S., Priebe S., Heiland I.,
RA Birringer M., Groth M., Segref A., Kanfi Y., Price N.L., Schmeisser S.,
RA Schuster S., Pfeiffer A.F., Guthke R., Platzer M., Hoppe T., Cohen H.Y.,
RA Zarse K., Sinclair D.A., Ristow M.;
RT "Role of sirtuins in lifespan regulation is linked to methylation of
RT nicotinamide.";
RL Nat. Chem. Biol. 9:693-700(2013).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23509272; DOI=10.1073/pnas.1214467110;
RA Ludewig A.H., Izrayelit Y., Park D., Malik R.U., Zimmermann A., Mahanti P.,
RA Fox B.W., Bethke A., Doering F., Riddle D.L., Schroeder F.C.;
RT "Pheromone sensing regulates Caenorhabditis elegans lifespan and stress
RT resistance via the deacetylase SIR-2.1.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:5522-5527(2013).
RN [11] {ECO:0000305}
RP FUNCTION.
RX PubMed=27514077; DOI=10.18632/aging.101011;
RA Nguyen T.T., Caito S.W., Zackert W.E., West J.D., Zhu S., Aschner M.,
RA Fessel J.P., Roberts L.J. II;
RT "Scavengers of reactive gamma-ketoaldehydes extend Caenorhabditis elegans
RT lifespan and healthspan through protein-level interactions with SIR-2.1 and
RT ETS-7.";
RL Aging (Albany NY) 8:1759-1780(2016).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=26598553; DOI=10.1242/jcs.174201;
RA Min H., Shim Y.H., Kawasaki I.;
RT "Loss of PGL-1 and PGL-3, members of a family of constitutive germ-granule
RT components, promotes germline apoptosis in C. elegans.";
RL J. Cell Sci. 129:341-353(2016).
RN [13]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=27650246; DOI=10.1038/srep33884;
RA Al-Amin M., Min H., Shim Y.H., Kawasaki I.;
RT "Somatically expressed germ-granule components, PGL-1 and PGL-3, repress
RT programmed cell death in C. elegans.";
RL Sci. Rep. 6:33884-33884(2016).
CC -!- FUNCTION: NAD-dependent deacetylase (By similarity). Involved in
CC metabolism, apoptosis, response to oxidative stress, response to DNA
CC damage, and determination of lifespan (PubMed:16777605,
CC PubMed:16280150, PubMed:16256736, PubMed:21909281, PubMed:23509272,
CC PubMed:24077178, PubMed:27514077, PubMed:26598553, PubMed:27650246).
CC Required for a reduction of the 'Lys-16' acetylation of histone H4
CC (H4K16ac) on dosage-compensated X chromosomes in hermaphrodites
CC (PubMed:22393255). Plays a role in germ cell and somatic cell apoptosis
CC in response to DNA damage (PubMed:26598553, PubMed:27650246). Functions
CC upstream of daf-16/Forkhead box protein O in the Insulin/IGF-1-like
CC signaling (IIS) mediated pathway, promoting daf-16 mediated
CC transcriptional activation and increased lifespan (PubMed:16777605,
CC PubMed:16280150). May also regulate lifespan independently of daf-16 by
CC modulating the transcription of genes involved in the stress response
CC of the endoplasmic reticulum (ER) (PubMed:16256736, PubMed:16280150).
CC Functions upstream of transcriptional coregulator hcf-1, perhaps acting
CC independently of the IIS mediated pathway, to modulate lifespan and
CC oxidative stress response (PubMed:21909281). Acts upstream of the
CC nicotinic acid metabolism pathway, which may be linked to the
CC regulation of longevity (PubMed:24077178). Plays a role in ascaroside-
CC mediated longevity and stress resistance (PubMed:23509272).
CC {ECO:0000250|UniProtKB:P06700, ECO:0000269|PubMed:11242085,
CC ECO:0000269|PubMed:15793589, ECO:0000269|PubMed:16256736,
CC ECO:0000269|PubMed:16280150, ECO:0000269|PubMed:16777605,
CC ECO:0000269|PubMed:21909281, ECO:0000269|PubMed:23509272,
CC ECO:0000269|PubMed:24077178, ECO:0000269|PubMed:26598553,
CC ECO:0000269|PubMed:27514077, ECO:0000269|PubMed:27650246}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-acetyl-L-lysyl-[protein] + NAD(+) = 2''-O-acetyl-
CC ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:43636, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10731,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:61930, ChEBI:CHEBI:83767;
CC EC=2.3.1.286; Evidence={ECO:0000255|PROSITE-ProRule:PRU00236};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P06700};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P06700};
CC -!- SUBUNIT: Interacts with ftt-2 and par-5 (PubMed:16777605). Interacts
CC with daf-16 following heat-shock, which causes daf-16 to accumulate in
CC the nucleus (PubMed:16777605). Interaction with daf-16 is promoted by
CC ftt-2 (PubMed:16777605). Interacts with transcriptional coregulator
CC hcf-1 (PubMed:21909281). {ECO:0000269|PubMed:16777605,
CC ECO:0000269|PubMed:21909281}.
CC -!- INTERACTION:
CC Q21921; O16850: daf-16; NbExp=2; IntAct=EBI-966082, EBI-324028;
CC Q21921; Q20655: ftt-2; NbExp=3; IntAct=EBI-966082, EBI-966073;
CC Q21921; P41932: par-5; NbExp=3; IntAct=EBI-966082, EBI-318108;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16280150,
CC ECO:0000269|PubMed:16777605, ECO:0000269|PubMed:26598553,
CC ECO:0000269|PubMed:27650246}. Cytoplasm {ECO:0000269|PubMed:26598553,
CC ECO:0000269|PubMed:27650246}. Note=Translocates from the nucleus to the
CC cytoplasm during apoptosis. {ECO:0000269|PubMed:26598553,
CC ECO:0000269|PubMed:27650246}.
CC -!- DEVELOPMENTAL STAGE: Expressed in neurons of the head and tail from
CC embryo to adult. Expressed in the hypodermis from the three-fold stage
CC of embryogenesis; expression in the hypodermis subsequently decreases
CC at L3 and is undetectable in adults. {ECO:0000269|PubMed:16280150}.
CC -!- DISRUPTION PHENOTYPE: Reduces the longevity-extending effects of
CC nicotinic acid when exposed to 1 mM nicotinic acid (PubMed:24077178).
CC Defective ascaroside-mediated responses with neither ascr#2 nor ascr#3
CC inducing lifespan extension or conferring thermotolerance
CC (PubMed:23509272). Reduced germ cell apoptosis in the gonadal arms
CC following DNA damage induced by UV-irradiation (PubMed:26598553). RNAi-
CC mediated depletion results in an increase of 'Lys-16' acetylation of
CC histone H4 (H4K16ac) on dosage-compensated X chromosomes in
CC hermaphrodites (PubMed:22393255). {ECO:0000269|PubMed:22393255,
CC ECO:0000269|PubMed:23509272, ECO:0000269|PubMed:24077178,
CC ECO:0000269|PubMed:26598553}.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class I subfamily.
CC {ECO:0000305}.
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DR EMBL; Z70310; CAA94364.1; -; Genomic_DNA.
DR PIR; T24172; T24172.
DR RefSeq; NP_001255484.1; NM_001268555.1.
DR AlphaFoldDB; Q21921; -.
DR SMR; Q21921; -.
DR BioGRID; 43026; 5.
DR ComplexPortal; CPX-3883; daf-16-sir-2.1 complex.
DR ComplexPortal; CPX-3885; sir-2.1-ftt-2 complex.
DR ComplexPortal; CPX-3886; sir-2.1-par-5 complex.
DR IntAct; Q21921; 3.
DR STRING; 6239.R11A8.4a; -.
DR iPTMnet; Q21921; -.
DR EPD; Q21921; -.
DR PaxDb; Q21921; -.
DR EnsemblMetazoa; R11A8.4a.1; R11A8.4a.1; WBGene00004800.
DR GeneID; 177924; -.
DR KEGG; cel:CELE_R11A8.4; -.
DR UCSC; R11A8.4.1; c. elegans.
DR CTD; 177924; -.
DR WormBase; R11A8.4a; CE06302; WBGene00004800; sir-2.1.
DR eggNOG; KOG2684; Eukaryota.
DR GeneTree; ENSGT00940000159406; -.
DR InParanoid; Q21921; -.
DR OMA; FSKCTCT; -.
DR OrthoDB; 973532at2759; -.
DR PhylomeDB; Q21921; -.
DR Reactome; R-CEL-3371453; Regulation of HSF1-mediated heat shock response.
DR Reactome; R-CEL-427359; SIRT1 negatively regulates rRNA expression.
DR Reactome; R-CEL-9617629; Regulation of FOXO transcriptional activity by acetylation.
DR SignaLink; Q21921; -.
DR PRO; PR:Q21921; -.
DR Proteomes; UP000001940; Chromosome IV.
DR Bgee; WBGene00004800; Expressed in embryo and 4 other tissues.
DR ExpressionAtlas; Q21921; baseline and differential.
DR GO; GO:0000781; C:chromosome, telomeric region; IDA:WormBase.
DR GO; GO:0005737; C:cytoplasm; IDA:WormBase.
DR GO; GO:0005637; C:nuclear inner membrane; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IDA:WormBase.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:WormBase.
DR GO; GO:0033553; C:rDNA heterochromatin; IBA:GO_Central.
DR GO; GO:0019213; F:deacetylase activity; IDA:WormBase.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070403; F:NAD+ binding; IBA:GO_Central.
DR GO; GO:0017136; F:NAD-dependent histone deacetylase activity; IBA:GO_Central.
DR GO; GO:0002039; F:p53 binding; IBA:GO_Central.
DR GO; GO:0003714; F:transcription corepressor activity; IBA:GO_Central.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0034605; P:cellular response to heat; IC:ComplexPortal.
DR GO; GO:0040024; P:dauer larval development; IGI:WormBase.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:WormBase.
DR GO; GO:0070932; P:histone H3 deacetylation; IDA:WormBase.
DR GO; GO:0043970; P:histone H3-K9 acetylation; IDA:WormBase.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:WormBase.
DR GO; GO:0051457; P:maintenance of protein location in nucleus; IC:ComplexPortal.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IBA:GO_Central.
DR GO; GO:0010628; P:positive regulation of gene expression; IC:ComplexPortal.
DR GO; GO:0006476; P:protein deacetylation; IDA:WormBase.
DR GO; GO:0010468; P:regulation of gene expression; IC:ComplexPortal.
DR Gene3D; 3.30.1600.10; -; 1.
DR InterPro; IPR029035; DHS-like_NAD/FAD-binding_dom.
DR InterPro; IPR003000; Sirtuin.
DR InterPro; IPR026591; Sirtuin_cat_small_dom_sf.
DR InterPro; IPR026590; Ssirtuin_cat_dom.
DR Pfam; PF02146; SIR2; 1.
DR SUPFAM; SSF52467; SSF52467; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Metal-binding; NAD; Nucleus; Reference proteome; Transferase;
KW Zinc.
FT CHAIN 1..607
FT /note="NAD-dependent protein deacetylase sir-2.1"
FT /id="PRO_0000249599"
FT DOMAIN 136..385
FT /note="Deacetylase sirtuin-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT REGION 1..68
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 426..453
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 28..68
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 255
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 153..172
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P06700"
FT BINDING 237..240
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P53686"
FT BINDING 263
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 266
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 287
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 290
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 327..329
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P06700"
FT BINDING 352..354
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P06700"
FT BINDING 369
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P06700"
SQ SEQUENCE 607 AA; 68766 MW; 71C720BAB41DC88D CRC64;
MSRDSGNDSE VAVTHGEVQE ITEENPEIGS MHITQETDIS DAPETNTDSS RQRTESTTSV
SSESWQNNDE MMSNLRRAQR LLDDGATPLQ IIQQIFPDFN ASRIATMSEN AHFAILSDLL
ERAPVRQKLT NYNSLADAVE LFKTKKHILV LTGAGVSVSC GIPDFRSKDG IYARLRSEFP
DLPDPTAMFD IRYFRENPAP FYNFAREIFP GQFVPSVSHR FIKELETSGR LLRNYTQNID
TLEHQTGIKR VVECHGSFSK CTCTRCGQKY DGNEIREEVL AMRVAHCKRC EGVIKPNIVF
FGEDLGREFH QHVTEDKHKV DLIVVIGSSL KVRPVALIPH CVDKNVPQIL INRESLPHYN
ADIELLGNCD DIIRDICFSL GGSFTELITS YDSIMEQQGK TKSQKPSQNK RQLISQEDFL
NICMKEKRND DSSDEPTLKK PRMSVADDSM DSEKNNFQEI QKHKSEDDDD TRNSDDILKK
IKHPRLLSIT EMLHDNKCVA ISAHQTVFPG AECSFDLETL KLVRDVHHET HCESSCGSSC
SSNADSEANQ LSRAQSLDDF VLSDEDRKNT IHLDLQRADS CDGDFQYELS ETIDPETFSH
LCEEMRI
