Full text data of SIRT2
SIRT2
(SIR2L, SIR2L2)
[Confidence: low (only semi-automatic identification from reviews)]
NAD-dependent protein deacetylase sirtuin-2; 3.5.1.- (Regulatory protein SIR2 homolog 2; SIR2-like protein 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
NAD-dependent protein deacetylase sirtuin-2; 3.5.1.- (Regulatory protein SIR2 homolog 2; SIR2-like protein 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q8IXJ6
ID SIR2_HUMAN Reviewed; 389 AA.
AC Q8IXJ6; A8K3V1; B2RB45; O95889; Q924Y7; Q9P0G8; Q9UNT0; Q9Y6E9;
read moreDT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2003, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=NAD-dependent protein deacetylase sirtuin-2;
DE EC=3.5.1.-;
DE AltName: Full=Regulatory protein SIR2 homolog 2;
DE AltName: Full=SIR2-like protein 2;
GN Name=SIRT2; Synonyms=SIR2L, SIR2L2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF HIS-187.
RC TISSUE=Testis;
RX PubMed=10381378; DOI=10.1006/bbrc.1999.0897;
RA Frye R.A.;
RT "Characterization of five human cDNAs with homology to the yeast SIR2
RT gene: Sir2-like proteins (sirtuins) metabolize NAD and may have
RT protein ADP-ribosyltransferase activity.";
RL Biochem. Biophys. Res. Commun. 260:273-279(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=10393250; DOI=10.1016/S0378-1119(99)00162-6;
RA Afshar G., Murnane J.P.;
RT "Characterization of a human gene with sequence homology to
RT Saccharomyces cerevisiae SIR2.";
RL Gene 234:161-168(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=12065666; DOI=10.1046/j.1471-4159.2002.00847.x;
RA De Smet C., Nishimori H., Furnari F.B., Boegler O., Huang H.-J.S.,
RA Cavenee W.K.;
RT "A novel seven transmembrane receptor induced during the early steps
RT of astrocyte differentiation identified by differential expression.";
RL J. Neurochem. 81:575-588(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Lennerz V., Fatho M., Gentilini C., Lifke A., Woelfel C., Woelfel T.;
RT "Response of autologous T cells to a human melanoma is dominated by
RT individual mutant antigens.";
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Adrenal gland;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Lung;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 22-389 (ISOFORM 4).
RC TISSUE=Brain;
RA Mei G., Yu W., Gibbs R.A.;
RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP INHIBITION BY SIRTINOL; A3 AND M15.
RX PubMed=11483616; DOI=10.1074/jbc.M106779200;
RA Grozinger C.M., Chao E.D., Blackwell H.E., Moazed D., Schreiber S.L.;
RT "Identification of a class of small molecule inhibitors of the sirtuin
RT family of NAD-dependent deacetylases by phenotypic screening.";
RL J. Biol. Chem. 276:38837-38843(2001).
RN [11]
RP CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-187.
RX PubMed=11812793; DOI=10.1074/jbc.M111830200;
RA Borra M.T., O'Neill F.J., Jackson M.D., Marshall B.L., Verdin E.,
RA Foltz K.R., Denu J.M.;
RT "Conserved enzymatic production and biological effect of O-acetyl-ADP-
RT ribose by silent information regulator 2-like NAD+-dependent
RT deacetylases.";
RL J. Biol. Chem. 277:12632-12641(2002).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HDAC6, AND
RP MUTAGENESIS OF ASN-168 AND HIS-187.
RX PubMed=12620231; DOI=10.1016/S1097-2765(03)00038-8;
RA North B.J., Marshall B.L., Borra M.T., Denu J.M., Verdin E.;
RT "The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin
RT deacetylase.";
RL Mol. Cell 11:437-444(2003).
RN [13]
RP FUNCTION, DEVELOPMENTAL STAGE, PHOSPHORYLATION, AND MUTAGENESIS OF
RP HIS-187.
RX PubMed=12697818; DOI=10.1128/MCB.23.9.3173-3185.2003;
RA Dryden S.C., Nahhas F.A., Nowak J.E., Goustin A.-S., Tainsky M.A.;
RT "Role for human SIRT2 NAD-dependent deacetylase activity in control of
RT mitotic exit in the cell cycle.";
RL Mol. Cell. Biol. 23:3173-3185(2003).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=12963026; DOI=10.1016/j.bbrc.2003.08.029;
RA Hiratsuka M., Inoue T., Toda T., Kimura N., Shirayoshi Y.,
RA Kamitani H., Watanabe T., Ohama E., Tahimic C.G.T., Kurimasa A.,
RA Oshimura M.;
RT "Proteomics-based identification of differentially expressed genes in
RT human gliomas: down-regulation of SIRT2 gene.";
RL Biochem. Biophys. Res. Commun. 309:558-566(2003).
RN [15]
RP SUBCELLULAR LOCATION.
RX PubMed=16079181; DOI=10.1091/mbc.E05-01-0033;
RA Michishita E., Park J.Y., Burneskis J.M., Barrett J.C., Horikawa I.;
RT "Evolutionarily conserved and nonconserved cellular localizations and
RT functions of human SIRT proteins.";
RL Mol. Biol. Cell 16:4623-4635(2005).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP FUNCTION, AND DEACETYLATION OF RELA.
RX PubMed=21081649; DOI=10.1242/jcs.073783;
RA Rothgiesser K.M., Erener S., Waibel S., Luscher B., Hottiger M.O.;
RT "SIRT2 regulates NF-kappaB dependent gene expression through
RT deacetylation of p65 Lys310.";
RL J. Cell Sci. 123:4251-4258(2010).
RN [21]
RP FUNCTION, AND DEACETYLATION OF PCK1.
RX PubMed=21726808; DOI=10.1016/j.molcel.2011.04.028;
RA Jiang W., Wang S., Xiao M., Lin Y., Zhou L., Lei Q., Xiong Y.,
RA Guan K.L., Zhao S.;
RT "Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation
RT via recruiting the UBR5 ubiquitin ligase.";
RL Mol. Cell 43:33-44(2011).
RN [22]
RP FUNCTION.
RX PubMed=23932781; DOI=10.1016/j.molcel.2013.07.002;
RA Lin R., Tao R., Gao X., Li T., Zhou X., Guan K.L., Xiong Y., Lei Q.Y.;
RT "Acetylation stabilizes ATP-citrate lyase to promote lipid
RT biosynthesis and tumor growth.";
RL Mol. Cell 51:506-518(2013).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 34-356 IN COMPLEX WITH ZINC,
RP AND MUTAGENESIS OF ARG-97; GLN-167; ASN-168; ASP-170 AND HIS-187.
RX PubMed=11427894; DOI=10.1038/89668;
RA Finnin M.S., Donigian J.R., Pavletich N.P.;
RT "Structure of the histone deacetylase SIRT2.";
RL Nat. Struct. Biol. 8:621-625(2001).
CC -!- FUNCTION: NAD-dependent protein deacetylase, which deacetylates
CC internal lysines on histone and non-histone proteins such as ACLY,
CC PCK1 and RELA. Deacetylates 'Lys-40' of alpha-tubulin. Involved in
CC the control of mitotic exit in the cell cycle, probably via its
CC role in the regulation of cytoskeleton. Deacetylates PCK1,
CC opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.
CC -!- CATALYTIC ACTIVITY: NAD(+) + an acetylprotein = nicotinamide + O-
CC acetyl-ADP-ribose + a protein.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- ENZYME REGULATION: Inhibited by Sirtinol, A3 and M15 small
CC molecules. Inhibited by nicotinamide.
CC -!- SUBUNIT: Interacts with HDAC6, suggesting that these proteins
CC belong to a large complex that deacetylate the cytoskeleton.
CC -!- INTERACTION:
CC O60729:CDC14B; NbExp=2; IntAct=EBI-477232, EBI-970231;
CC Q12834:CDC20; NbExp=2; IntAct=EBI-5240785, EBI-367462;
CC Q9UM11:FZR1; NbExp=2; IntAct=EBI-5240785, EBI-724997;
CC Q92831:KAT2B; NbExp=4; IntAct=EBI-477232, EBI-477430;
CC Q9Y572:RIPK3; NbExp=2; IntAct=EBI-477232, EBI-298250;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Note=Colocalizes
CC with microtubules.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q8IXJ6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IXJ6-2; Sequence=VSP_008724;
CC Name=3;
CC IsoId=Q8IXJ6-3; Sequence=VSP_008726;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q8IXJ6-4; Sequence=VSP_008727, VSP_008728;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in heart,
CC brain and skeletal muscle, while it is weakly expressed in
CC placenta and lung. Down-regulated in many gliomas suggesting that
CC it may act as a tumor suppressor gene in human gliomas possibly
CC through the regulation of microtubule network.
CC -!- DEVELOPMENTAL STAGE: Peaks during mitosis. After mitosis, it is
CC probably degraded by the 26S proteasome.
CC -!- PTM: Phosphorylated at the G2/M transition of the cell cycle.
CC -!- MISCELLANEOUS: Has some ability to deacetylate histones in vitro,
CC but seeing its subcellular location, this is unlikely in vivo.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class I subfamily.
CC -!- SIMILARITY: Contains 1 deacetylase sirtuin-type domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD45971.1; Type=Erroneous initiation;
CC Sequence=AAF67015.1; Type=Frameshift; Positions=Several;
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DR EMBL; AF083107; AAD40850.2; -; mRNA.
DR EMBL; AF095714; AAD45971.1; ALT_INIT; mRNA.
DR EMBL; AY030277; AAK51133.1; -; mRNA.
DR EMBL; AJ505014; CAD43717.1; -; mRNA.
DR EMBL; AF160214; AAF67015.1; ALT_FRAME; mRNA.
DR EMBL; AK290716; BAF83405.1; -; mRNA.
DR EMBL; AK314492; BAG37092.1; -; mRNA.
DR EMBL; CH471126; EAW56833.1; -; Genomic_DNA.
DR EMBL; CH471126; EAW56835.1; -; Genomic_DNA.
DR EMBL; BC003012; AAH03012.1; -; mRNA.
DR EMBL; BC003547; AAH03547.1; -; mRNA.
DR EMBL; AF131800; AAD20046.1; -; mRNA.
DR RefSeq; NP_001180215.1; NM_001193286.1.
DR RefSeq; NP_036369.2; NM_012237.3.
DR RefSeq; NP_085096.1; NM_030593.2.
DR UniGene; Hs.466693; -.
DR PDB; 1J8F; X-ray; 1.70 A; A/B/C=34-356.
DR PDB; 3ZGO; X-ray; 1.63 A; A/B/C=34-356.
DR PDB; 3ZGV; X-ray; 2.27 A; A/B=34-356.
DR PDBsum; 1J8F; -.
DR PDBsum; 3ZGO; -.
DR PDBsum; 3ZGV; -.
DR ProteinModelPortal; Q8IXJ6; -.
DR SMR; Q8IXJ6; 54-356.
DR DIP; DIP-33350N; -.
DR IntAct; Q8IXJ6; 14.
DR MINT; MINT-3037896; -.
DR STRING; 9606.ENSP00000249396; -.
DR BindingDB; Q8IXJ6; -.
DR ChEMBL; CHEMBL4462; -.
DR PhosphoSite; Q8IXJ6; -.
DR DMDM; 38258608; -.
DR PaxDb; Q8IXJ6; -.
DR PRIDE; Q8IXJ6; -.
DR DNASU; 22933; -.
DR Ensembl; ENST00000249396; ENSP00000249396; ENSG00000068903.
DR Ensembl; ENST00000358931; ENSP00000351809; ENSG00000068903.
DR Ensembl; ENST00000392081; ENSP00000375931; ENSG00000068903.
DR GeneID; 22933; -.
DR KEGG; hsa:22933; -.
DR UCSC; uc002ojt.2; human.
DR CTD; 22933; -.
DR GeneCards; GC19M039369; -.
DR HGNC; HGNC:10886; SIRT2.
DR HPA; CAB004573; -.
DR HPA; HPA011165; -.
DR MIM; 604480; gene.
DR neXtProt; NX_Q8IXJ6; -.
DR PharmGKB; PA35786; -.
DR eggNOG; COG0846; -.
DR HOVERGEN; HBG057095; -.
DR KO; K11412; -.
DR OMA; TICHYFM; -.
DR OrthoDB; EOG7WX09C; -.
DR PhylomeDB; Q8IXJ6; -.
DR SABIO-RK; Q8IXJ6; -.
DR ChiTaRS; SIRT2; human.
DR EvolutionaryTrace; Q8IXJ6; -.
DR GeneWiki; SIRT2; -.
DR GenomeRNAi; 22933; -.
DR NextBio; 43669; -.
DR PRO; PR:Q8IXJ6; -.
DR ArrayExpress; Q8IXJ6; -.
DR Bgee; Q8IXJ6; -.
DR CleanEx; HS_SIRT2; -.
DR Genevestigator; Q8IXJ6; -.
DR GO; GO:0005677; C:chromatin silencing complex; NAS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0070403; F:NAD+ binding; IDA:UniProtKB.
DR GO; GO:0017136; F:NAD-dependent histone deacetylase activity; IDA:UniProtKB.
DR GO; GO:0042903; F:tubulin deacetylase activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0000183; P:chromatin silencing at rDNA; NAS:UniProtKB.
DR GO; GO:0006348; P:chromatin silencing at telomere; NAS:UniProtKB.
DR GO; GO:0007067; P:mitosis; IEA:UniProtKB-KW.
DR GO; GO:0045843; P:negative regulation of striated muscle tissue development; IDA:UniProtKB.
DR GO; GO:0034983; P:peptidyl-lysine deacetylation; IDA:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0006471; P:protein ADP-ribosylation; NAS:UniProtKB.
DR GO; GO:0007096; P:regulation of exit from mitosis; NAS:UniProtKB.
DR GO; GO:0042325; P:regulation of phosphorylation; NAS:UniProtKB.
DR GO; GO:0051775; P:response to redox state; NAS:UniProtKB.
DR InterPro; IPR003000; Sirtuin.
DR InterPro; IPR017328; Sirtuin_class_I.
DR InterPro; IPR026590; Ssirtuin_cat_dom.
DR PANTHER; PTHR11085; PTHR11085; 1.
DR Pfam; PF02146; SIR2; 1.
DR PIRSF; PIRSF037938; SIR2_euk; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell cycle;
KW Cell division; Complete proteome; Cytoplasm; Cytoskeleton; Hydrolase;
KW Metal-binding; Microtubule; Mitosis; NAD; Phosphoprotein;
KW Reference proteome; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 389 NAD-dependent protein deacetylase
FT sirtuin-2.
FT /FTId=PRO_0000110258.
FT DOMAIN 65 340 Deacetylase sirtuin-type.
FT NP_BIND 84 104 NAD (By similarity).
FT NP_BIND 167 170 NAD (By similarity).
FT NP_BIND 261 263 NAD (By similarity).
FT NP_BIND 286 288 NAD (By similarity).
FT ACT_SITE 187 187 Proton acceptor.
FT METAL 195 195 Zinc.
FT METAL 200 200 Zinc.
FT METAL 221 221 Zinc.
FT METAL 224 224 Zinc.
FT BINDING 324 324 NAD; via amide nitrogen (By similarity).
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 1 38 MAEPDPSHPLETQAGKVQEAQDSDSDSEGGAAGGEADM ->
FT MPLAECPSCRCLSSFRSV (in isoform 3).
FT /FTId=VSP_008726.
FT VAR_SEQ 1 37 Missing (in isoform 2).
FT /FTId=VSP_008724.
FT VAR_SEQ 266 271 VQPFAS -> GRGLAG (in isoform 4).
FT /FTId=VSP_008727.
FT VAR_SEQ 272 389 Missing (in isoform 4).
FT /FTId=VSP_008728.
FT MUTAGEN 97 97 R->A: No effect on deacetylase activity.
FT MUTAGEN 167 167 Q->A: Reduced deacetylase activity.
FT MUTAGEN 168 168 N->A: Abolishes acetylation of alpha-
FT tubulin.
FT MUTAGEN 170 170 D->A,N: Reduced deacetylase activity.
FT MUTAGEN 187 187 H->Y,A: Loss of function. Abolishes
FT acetylation of alpha-tubulin. No effect
FT on phosphorylation.
FT CONFLICT 199 199 S -> N (in Ref. 5).
FT CONFLICT 219 219 P -> L (in Ref. 4; CAD43717).
FT HELIX 35 45
FT STRAND 60 63
FT HELIX 64 71
FT STRAND 73 75
FT STRAND 79 83
FT HELIX 85 87
FT HELIX 89 91
FT STRAND 96 98
FT TURN 99 101
FT HELIX 105 110
FT HELIX 115 119
FT HELIX 121 126
FT HELIX 129 138
FT STRAND 139 142
FT HELIX 147 157
FT STRAND 161 166
FT HELIX 172 175
FT HELIX 180 182
FT STRAND 183 185
FT STRAND 188 196
FT TURN 198 200
FT HELIX 206 215
FT TURN 222 224
FT STRAND 227 232
FT HELIX 242 249
FT HELIX 250 252
FT STRAND 255 262
FT HELIX 269 275
FT STRAND 282 288
FT HELIX 295 303
FT STRAND 309 311
FT STRAND 316 322
FT HELIX 324 335
FT HELIX 338 355
SQ SEQUENCE 389 AA; 43182 MW; A392442A8F6316F1 CRC64;
MAEPDPSHPL ETQAGKVQEA QDSDSDSEGG AAGGEADMDF LRNLFSQTLS LGSQKERLLD
ELTLEGVARY MQSERCRRVI CLVGAGISTS AGIPDFRSPS TGLYDNLEKY HLPYPEAIFE
ISYFKKHPEP FFALAKELYP GQFKPTICHY FMRLLKDKGL LLRCYTQNID TLERIAGLEQ
EDLVEAHGTF YTSHCVSASC RHEYPLSWMK EKIFSEVTPK CEDCQSLVKP DIVFFGESLP
ARFFSCMQSD FLKVDLLLVM GTSLQVQPFA SLISKAPLST PRLLINKEKA GQSDPFLGMI
MGLGGGMDFD SKKAYRDVAW LGECDQGCLA LAELLGWKKE LEDLVRREHA SIDAQSGAGV
PNPSTSASPK KSPPPAKDEA RTTEREKPQ
//
ID SIR2_HUMAN Reviewed; 389 AA.
AC Q8IXJ6; A8K3V1; B2RB45; O95889; Q924Y7; Q9P0G8; Q9UNT0; Q9Y6E9;
read moreDT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2003, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=NAD-dependent protein deacetylase sirtuin-2;
DE EC=3.5.1.-;
DE AltName: Full=Regulatory protein SIR2 homolog 2;
DE AltName: Full=SIR2-like protein 2;
GN Name=SIRT2; Synonyms=SIR2L, SIR2L2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF HIS-187.
RC TISSUE=Testis;
RX PubMed=10381378; DOI=10.1006/bbrc.1999.0897;
RA Frye R.A.;
RT "Characterization of five human cDNAs with homology to the yeast SIR2
RT gene: Sir2-like proteins (sirtuins) metabolize NAD and may have
RT protein ADP-ribosyltransferase activity.";
RL Biochem. Biophys. Res. Commun. 260:273-279(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=10393250; DOI=10.1016/S0378-1119(99)00162-6;
RA Afshar G., Murnane J.P.;
RT "Characterization of a human gene with sequence homology to
RT Saccharomyces cerevisiae SIR2.";
RL Gene 234:161-168(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=12065666; DOI=10.1046/j.1471-4159.2002.00847.x;
RA De Smet C., Nishimori H., Furnari F.B., Boegler O., Huang H.-J.S.,
RA Cavenee W.K.;
RT "A novel seven transmembrane receptor induced during the early steps
RT of astrocyte differentiation identified by differential expression.";
RL J. Neurochem. 81:575-588(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Lennerz V., Fatho M., Gentilini C., Lifke A., Woelfel C., Woelfel T.;
RT "Response of autologous T cells to a human melanoma is dominated by
RT individual mutant antigens.";
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Adrenal gland;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Lung;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 22-389 (ISOFORM 4).
RC TISSUE=Brain;
RA Mei G., Yu W., Gibbs R.A.;
RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP INHIBITION BY SIRTINOL; A3 AND M15.
RX PubMed=11483616; DOI=10.1074/jbc.M106779200;
RA Grozinger C.M., Chao E.D., Blackwell H.E., Moazed D., Schreiber S.L.;
RT "Identification of a class of small molecule inhibitors of the sirtuin
RT family of NAD-dependent deacetylases by phenotypic screening.";
RL J. Biol. Chem. 276:38837-38843(2001).
RN [11]
RP CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-187.
RX PubMed=11812793; DOI=10.1074/jbc.M111830200;
RA Borra M.T., O'Neill F.J., Jackson M.D., Marshall B.L., Verdin E.,
RA Foltz K.R., Denu J.M.;
RT "Conserved enzymatic production and biological effect of O-acetyl-ADP-
RT ribose by silent information regulator 2-like NAD+-dependent
RT deacetylases.";
RL J. Biol. Chem. 277:12632-12641(2002).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HDAC6, AND
RP MUTAGENESIS OF ASN-168 AND HIS-187.
RX PubMed=12620231; DOI=10.1016/S1097-2765(03)00038-8;
RA North B.J., Marshall B.L., Borra M.T., Denu J.M., Verdin E.;
RT "The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin
RT deacetylase.";
RL Mol. Cell 11:437-444(2003).
RN [13]
RP FUNCTION, DEVELOPMENTAL STAGE, PHOSPHORYLATION, AND MUTAGENESIS OF
RP HIS-187.
RX PubMed=12697818; DOI=10.1128/MCB.23.9.3173-3185.2003;
RA Dryden S.C., Nahhas F.A., Nowak J.E., Goustin A.-S., Tainsky M.A.;
RT "Role for human SIRT2 NAD-dependent deacetylase activity in control of
RT mitotic exit in the cell cycle.";
RL Mol. Cell. Biol. 23:3173-3185(2003).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=12963026; DOI=10.1016/j.bbrc.2003.08.029;
RA Hiratsuka M., Inoue T., Toda T., Kimura N., Shirayoshi Y.,
RA Kamitani H., Watanabe T., Ohama E., Tahimic C.G.T., Kurimasa A.,
RA Oshimura M.;
RT "Proteomics-based identification of differentially expressed genes in
RT human gliomas: down-regulation of SIRT2 gene.";
RL Biochem. Biophys. Res. Commun. 309:558-566(2003).
RN [15]
RP SUBCELLULAR LOCATION.
RX PubMed=16079181; DOI=10.1091/mbc.E05-01-0033;
RA Michishita E., Park J.Y., Burneskis J.M., Barrett J.C., Horikawa I.;
RT "Evolutionarily conserved and nonconserved cellular localizations and
RT functions of human SIRT proteins.";
RL Mol. Biol. Cell 16:4623-4635(2005).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP FUNCTION, AND DEACETYLATION OF RELA.
RX PubMed=21081649; DOI=10.1242/jcs.073783;
RA Rothgiesser K.M., Erener S., Waibel S., Luscher B., Hottiger M.O.;
RT "SIRT2 regulates NF-kappaB dependent gene expression through
RT deacetylation of p65 Lys310.";
RL J. Cell Sci. 123:4251-4258(2010).
RN [21]
RP FUNCTION, AND DEACETYLATION OF PCK1.
RX PubMed=21726808; DOI=10.1016/j.molcel.2011.04.028;
RA Jiang W., Wang S., Xiao M., Lin Y., Zhou L., Lei Q., Xiong Y.,
RA Guan K.L., Zhao S.;
RT "Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation
RT via recruiting the UBR5 ubiquitin ligase.";
RL Mol. Cell 43:33-44(2011).
RN [22]
RP FUNCTION.
RX PubMed=23932781; DOI=10.1016/j.molcel.2013.07.002;
RA Lin R., Tao R., Gao X., Li T., Zhou X., Guan K.L., Xiong Y., Lei Q.Y.;
RT "Acetylation stabilizes ATP-citrate lyase to promote lipid
RT biosynthesis and tumor growth.";
RL Mol. Cell 51:506-518(2013).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 34-356 IN COMPLEX WITH ZINC,
RP AND MUTAGENESIS OF ARG-97; GLN-167; ASN-168; ASP-170 AND HIS-187.
RX PubMed=11427894; DOI=10.1038/89668;
RA Finnin M.S., Donigian J.R., Pavletich N.P.;
RT "Structure of the histone deacetylase SIRT2.";
RL Nat. Struct. Biol. 8:621-625(2001).
CC -!- FUNCTION: NAD-dependent protein deacetylase, which deacetylates
CC internal lysines on histone and non-histone proteins such as ACLY,
CC PCK1 and RELA. Deacetylates 'Lys-40' of alpha-tubulin. Involved in
CC the control of mitotic exit in the cell cycle, probably via its
CC role in the regulation of cytoskeleton. Deacetylates PCK1,
CC opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.
CC -!- CATALYTIC ACTIVITY: NAD(+) + an acetylprotein = nicotinamide + O-
CC acetyl-ADP-ribose + a protein.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- ENZYME REGULATION: Inhibited by Sirtinol, A3 and M15 small
CC molecules. Inhibited by nicotinamide.
CC -!- SUBUNIT: Interacts with HDAC6, suggesting that these proteins
CC belong to a large complex that deacetylate the cytoskeleton.
CC -!- INTERACTION:
CC O60729:CDC14B; NbExp=2; IntAct=EBI-477232, EBI-970231;
CC Q12834:CDC20; NbExp=2; IntAct=EBI-5240785, EBI-367462;
CC Q9UM11:FZR1; NbExp=2; IntAct=EBI-5240785, EBI-724997;
CC Q92831:KAT2B; NbExp=4; IntAct=EBI-477232, EBI-477430;
CC Q9Y572:RIPK3; NbExp=2; IntAct=EBI-477232, EBI-298250;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Note=Colocalizes
CC with microtubules.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q8IXJ6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IXJ6-2; Sequence=VSP_008724;
CC Name=3;
CC IsoId=Q8IXJ6-3; Sequence=VSP_008726;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q8IXJ6-4; Sequence=VSP_008727, VSP_008728;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in heart,
CC brain and skeletal muscle, while it is weakly expressed in
CC placenta and lung. Down-regulated in many gliomas suggesting that
CC it may act as a tumor suppressor gene in human gliomas possibly
CC through the regulation of microtubule network.
CC -!- DEVELOPMENTAL STAGE: Peaks during mitosis. After mitosis, it is
CC probably degraded by the 26S proteasome.
CC -!- PTM: Phosphorylated at the G2/M transition of the cell cycle.
CC -!- MISCELLANEOUS: Has some ability to deacetylate histones in vitro,
CC but seeing its subcellular location, this is unlikely in vivo.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class I subfamily.
CC -!- SIMILARITY: Contains 1 deacetylase sirtuin-type domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD45971.1; Type=Erroneous initiation;
CC Sequence=AAF67015.1; Type=Frameshift; Positions=Several;
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DR EMBL; AF083107; AAD40850.2; -; mRNA.
DR EMBL; AF095714; AAD45971.1; ALT_INIT; mRNA.
DR EMBL; AY030277; AAK51133.1; -; mRNA.
DR EMBL; AJ505014; CAD43717.1; -; mRNA.
DR EMBL; AF160214; AAF67015.1; ALT_FRAME; mRNA.
DR EMBL; AK290716; BAF83405.1; -; mRNA.
DR EMBL; AK314492; BAG37092.1; -; mRNA.
DR EMBL; CH471126; EAW56833.1; -; Genomic_DNA.
DR EMBL; CH471126; EAW56835.1; -; Genomic_DNA.
DR EMBL; BC003012; AAH03012.1; -; mRNA.
DR EMBL; BC003547; AAH03547.1; -; mRNA.
DR EMBL; AF131800; AAD20046.1; -; mRNA.
DR RefSeq; NP_001180215.1; NM_001193286.1.
DR RefSeq; NP_036369.2; NM_012237.3.
DR RefSeq; NP_085096.1; NM_030593.2.
DR UniGene; Hs.466693; -.
DR PDB; 1J8F; X-ray; 1.70 A; A/B/C=34-356.
DR PDB; 3ZGO; X-ray; 1.63 A; A/B/C=34-356.
DR PDB; 3ZGV; X-ray; 2.27 A; A/B=34-356.
DR PDBsum; 1J8F; -.
DR PDBsum; 3ZGO; -.
DR PDBsum; 3ZGV; -.
DR ProteinModelPortal; Q8IXJ6; -.
DR SMR; Q8IXJ6; 54-356.
DR DIP; DIP-33350N; -.
DR IntAct; Q8IXJ6; 14.
DR MINT; MINT-3037896; -.
DR STRING; 9606.ENSP00000249396; -.
DR BindingDB; Q8IXJ6; -.
DR ChEMBL; CHEMBL4462; -.
DR PhosphoSite; Q8IXJ6; -.
DR DMDM; 38258608; -.
DR PaxDb; Q8IXJ6; -.
DR PRIDE; Q8IXJ6; -.
DR DNASU; 22933; -.
DR Ensembl; ENST00000249396; ENSP00000249396; ENSG00000068903.
DR Ensembl; ENST00000358931; ENSP00000351809; ENSG00000068903.
DR Ensembl; ENST00000392081; ENSP00000375931; ENSG00000068903.
DR GeneID; 22933; -.
DR KEGG; hsa:22933; -.
DR UCSC; uc002ojt.2; human.
DR CTD; 22933; -.
DR GeneCards; GC19M039369; -.
DR HGNC; HGNC:10886; SIRT2.
DR HPA; CAB004573; -.
DR HPA; HPA011165; -.
DR MIM; 604480; gene.
DR neXtProt; NX_Q8IXJ6; -.
DR PharmGKB; PA35786; -.
DR eggNOG; COG0846; -.
DR HOVERGEN; HBG057095; -.
DR KO; K11412; -.
DR OMA; TICHYFM; -.
DR OrthoDB; EOG7WX09C; -.
DR PhylomeDB; Q8IXJ6; -.
DR SABIO-RK; Q8IXJ6; -.
DR ChiTaRS; SIRT2; human.
DR EvolutionaryTrace; Q8IXJ6; -.
DR GeneWiki; SIRT2; -.
DR GenomeRNAi; 22933; -.
DR NextBio; 43669; -.
DR PRO; PR:Q8IXJ6; -.
DR ArrayExpress; Q8IXJ6; -.
DR Bgee; Q8IXJ6; -.
DR CleanEx; HS_SIRT2; -.
DR Genevestigator; Q8IXJ6; -.
DR GO; GO:0005677; C:chromatin silencing complex; NAS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0070403; F:NAD+ binding; IDA:UniProtKB.
DR GO; GO:0017136; F:NAD-dependent histone deacetylase activity; IDA:UniProtKB.
DR GO; GO:0042903; F:tubulin deacetylase activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0000183; P:chromatin silencing at rDNA; NAS:UniProtKB.
DR GO; GO:0006348; P:chromatin silencing at telomere; NAS:UniProtKB.
DR GO; GO:0007067; P:mitosis; IEA:UniProtKB-KW.
DR GO; GO:0045843; P:negative regulation of striated muscle tissue development; IDA:UniProtKB.
DR GO; GO:0034983; P:peptidyl-lysine deacetylation; IDA:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0006471; P:protein ADP-ribosylation; NAS:UniProtKB.
DR GO; GO:0007096; P:regulation of exit from mitosis; NAS:UniProtKB.
DR GO; GO:0042325; P:regulation of phosphorylation; NAS:UniProtKB.
DR GO; GO:0051775; P:response to redox state; NAS:UniProtKB.
DR InterPro; IPR003000; Sirtuin.
DR InterPro; IPR017328; Sirtuin_class_I.
DR InterPro; IPR026590; Ssirtuin_cat_dom.
DR PANTHER; PTHR11085; PTHR11085; 1.
DR Pfam; PF02146; SIR2; 1.
DR PIRSF; PIRSF037938; SIR2_euk; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell cycle;
KW Cell division; Complete proteome; Cytoplasm; Cytoskeleton; Hydrolase;
KW Metal-binding; Microtubule; Mitosis; NAD; Phosphoprotein;
KW Reference proteome; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 389 NAD-dependent protein deacetylase
FT sirtuin-2.
FT /FTId=PRO_0000110258.
FT DOMAIN 65 340 Deacetylase sirtuin-type.
FT NP_BIND 84 104 NAD (By similarity).
FT NP_BIND 167 170 NAD (By similarity).
FT NP_BIND 261 263 NAD (By similarity).
FT NP_BIND 286 288 NAD (By similarity).
FT ACT_SITE 187 187 Proton acceptor.
FT METAL 195 195 Zinc.
FT METAL 200 200 Zinc.
FT METAL 221 221 Zinc.
FT METAL 224 224 Zinc.
FT BINDING 324 324 NAD; via amide nitrogen (By similarity).
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 1 38 MAEPDPSHPLETQAGKVQEAQDSDSDSEGGAAGGEADM ->
FT MPLAECPSCRCLSSFRSV (in isoform 3).
FT /FTId=VSP_008726.
FT VAR_SEQ 1 37 Missing (in isoform 2).
FT /FTId=VSP_008724.
FT VAR_SEQ 266 271 VQPFAS -> GRGLAG (in isoform 4).
FT /FTId=VSP_008727.
FT VAR_SEQ 272 389 Missing (in isoform 4).
FT /FTId=VSP_008728.
FT MUTAGEN 97 97 R->A: No effect on deacetylase activity.
FT MUTAGEN 167 167 Q->A: Reduced deacetylase activity.
FT MUTAGEN 168 168 N->A: Abolishes acetylation of alpha-
FT tubulin.
FT MUTAGEN 170 170 D->A,N: Reduced deacetylase activity.
FT MUTAGEN 187 187 H->Y,A: Loss of function. Abolishes
FT acetylation of alpha-tubulin. No effect
FT on phosphorylation.
FT CONFLICT 199 199 S -> N (in Ref. 5).
FT CONFLICT 219 219 P -> L (in Ref. 4; CAD43717).
FT HELIX 35 45
FT STRAND 60 63
FT HELIX 64 71
FT STRAND 73 75
FT STRAND 79 83
FT HELIX 85 87
FT HELIX 89 91
FT STRAND 96 98
FT TURN 99 101
FT HELIX 105 110
FT HELIX 115 119
FT HELIX 121 126
FT HELIX 129 138
FT STRAND 139 142
FT HELIX 147 157
FT STRAND 161 166
FT HELIX 172 175
FT HELIX 180 182
FT STRAND 183 185
FT STRAND 188 196
FT TURN 198 200
FT HELIX 206 215
FT TURN 222 224
FT STRAND 227 232
FT HELIX 242 249
FT HELIX 250 252
FT STRAND 255 262
FT HELIX 269 275
FT STRAND 282 288
FT HELIX 295 303
FT STRAND 309 311
FT STRAND 316 322
FT HELIX 324 335
FT HELIX 338 355
SQ SEQUENCE 389 AA; 43182 MW; A392442A8F6316F1 CRC64;
MAEPDPSHPL ETQAGKVQEA QDSDSDSEGG AAGGEADMDF LRNLFSQTLS LGSQKERLLD
ELTLEGVARY MQSERCRRVI CLVGAGISTS AGIPDFRSPS TGLYDNLEKY HLPYPEAIFE
ISYFKKHPEP FFALAKELYP GQFKPTICHY FMRLLKDKGL LLRCYTQNID TLERIAGLEQ
EDLVEAHGTF YTSHCVSASC RHEYPLSWMK EKIFSEVTPK CEDCQSLVKP DIVFFGESLP
ARFFSCMQSD FLKVDLLLVM GTSLQVQPFA SLISKAPLST PRLLINKEKA GQSDPFLGMI
MGLGGGMDFD SKKAYRDVAW LGECDQGCLA LAELLGWKKE LEDLVRREHA SIDAQSGAGV
PNPSTSASPK KSPPPAKDEA RTTEREKPQ
//
MIM
604480
*RECORD*
*FIELD* NO
604480
*FIELD* TI
*604480 SIRTUIN 2; SIRT2
;;SIR2, S. CEREVISIAE, HOMOLOG-LIKE 2; SIR2L2;;
SIR2L
*FIELD* TX
read more
CLONING
The yeast Sir2 (silent information regulator-2) protein (Shore et al.,
1984) regulates epigenetic gene silencing and, as a possible antiaging
effect, suppresses recombination of rDNA. Studies involving cobB, a
bacterial Sir2-like gene, have suggested that Sir2 may encode a pyridine
nucleotide transferase. By in silico and PCR-cloning techniques, Frye
(1999) obtained cDNA sequences encoding 5 human Sir2-like genes, which
they called sirtuin-1 to -5 (SIRT1 to SIRT5). The SIRT1 (604479)
sequence has the closest homology to the S. cerevisiae Sir2 protein,
while SIRT4 (604482) and SIRT5 (604483) more closely resemble
prokaryotic sirtuin sequences. PCR analysis showed that the 5 human
sirtuins are widely expressed in fetal and adult tissues.
Afshar and Murnane (1999) sequenced a full-length SIRT2 (SIR2L) EST
clone. The deduced 352-amino acid protein has a calculated molecular
mass of 39.5 kD. It has 2 potential leucine zipper motifs, 6 possible
N-myristoylation sites, and several potential protein kinase C (see
PRKCA, 176960) phosphorylation sites. Northern blot analysis detected
variable expression of a 2.1-kb transcript in all tissues examined, with
higher expression in heart, brain, and skeletal muscle, and lower
expression in placenta and lung. Fluorescence-tagged SIRT2 localized
primarily in the cytoplasm of transfected human fibroblasts and a tumor
cell line.
GENE FUNCTION
Frye (1999) found that recombinant human SIRT2 was able to cause
radioactivity to be transferred from (32P)NAD to bovine serum albumin
(BSA). When a conserved histidine within SIRT2 was converted to
tyrosine, the mutant recombinant protein was unable to transfer
radioactivity from (32P)NAD to BSA. These results suggested that the
sirtuins may function via mono-ADP-ribosylation of proteins.
Tanny et al. (1999) showed that the yeast Sir2 protein can transfer
labeled phosphate from nicotinamide adenine dinucleotide to itself and
histones in vitro. A modified form of Sir2, which results from its
automodification activity, was specifically recognized by
anti-mono-ADP-ribose antibodies, suggesting that Sir2 is an
ADP-ribosyltransferase. Mutation of a phylogenetically invariant
histidine (his364 to tyr) in Sir2 abolished both its enzymatic activity
in vitro and its silencing functions in vivo. However, the mutant
protein was associated with chromatin and other silencing factors in a
manner similar to wildtype Sir2. These findings suggested that Sir2
contains an ADP-ribosyltransferase activity that is essential for its
silencing function.
Rogina et al. (2002) found that under 2 life-extending conditions, Rpd3
(601241) mutants fed normal food and wildtype flies fed low calorie
food, Sir2 expression was increased 2-fold.
Carbonylated proteins, which are a sign of irreversible oxidative
damage, were visualized in single cells of S. cerevisiae, revealing that
they accumulate with replicative age. Aguilaniu et al. (2003) showed the
carbonylated proteins were not inherited by daughter cells during
cytokinesis. Mother cells of a yeast strain lacking the Sir2 gene, a
life-span determinant, failed to retain oxidatively damaged proteins
during cytokinesis. Aguilaniu et al. (2003) concluded that a genetically
determined, SIR2-dependent asymmetric inheritance of oxidatively damaged
proteins may contribute to free-radical defense and the fitness of
newborn cells.
North et al. (2003) reported that SIRT2 is a predominantly cytoplasmic
protein that colocalizes with microtubules. SIRT2 was found to
deacetylate lys40 of alpha-tubulin (602530) both in vitro and in vivo.
Knockdown of SIRT2 via small interfering RNA resulted in tubulin
hyperacetylation. SIRT2 colocalized and interacted in vivo with HDAC6
(300272), another tubulin deacetylase. Enzymatic analysis of recombinant
SIRT2 in comparison to a yeast homolog of Sir2 protein showed a striking
preference of SIRT2 for acetylated tubulin peptide as a substrate
relative to acetylated histone H3 peptide. These observations
established SIRT2 as a bona fide tubulin deacetylase.
By Western blot analysis of a human osteosarcoma cell line, Dryden et
al. (2003) resolved SIRT2 into isoforms of about 48 kD and above that
differed in their degree of phosphorylation. Using synchronized cells,
they found that the hyperphosphorylated forms of SIRT2 were confined to
the M phase of the cell cycle, coincident with the G2/M transition, and
maintained throughout the M phase. Overexpression of SIRT2 resulted in
increased NAD-dependent deacetylase activity and delayed cell cycle
progression through mitosis. Overexpression of CDC14B (603505), but not
CDC14A (603504) or a CDC14B mutant lacking phosphatase activity, led to
the loss of hyperphosphorylated SIRT2. In the presence of other mitotic
regulators, such as B-type cyclins (see 123836), SIRT2 became
ubiquitinated and was degraded via the 26S proteasome pathway. Dryden et
al. (2003) concluded that SIRT2 is a regulator of mitotic progression
that acts downstream from CDC14B in a pathway regulating mitotic exit or
subsequent cytokinesis.
By mutation analysis, Sherman et al. (1999) found that the conserved
core domain of SIR2 proteins, which includes 2 sequence motifs and 4
cysteines of a putative zinc finger, is essential for gene silencing.
Chimeras between yeast and human SIR2 homologs showed that the human
core domain can substitute for that of yeast, confirming that the
conserved core is a silencing domain.
Outeiro et al. (2007) identified a potent inhibitor of SIRT2 and found
that inhibition of SIRT2 rescued alpha-synuclein (163890) toxicity and
modified inclusion morphology in a cellular model of Parkinson disease
(168600). Genetic inhibition of SIRT2 via small interfering RNA
similarly rescued alpha-synuclein toxicity. The inhibitors protected
against dopaminergic cell death both in vitro and in a Drosophila model
of Parkinson disease. Outeiro et al. (2007) concluded that their results
suggest a link between neurodegeneration and aging.
Das et al. (2009) demonstrated that the histone acetyltransferase CBP
(600140) in flies, and CBP and p300 in humans, acetylate histone H3 on
lys56 (H3K56), whereas Drosophila sir2 and human SIRT1 (604479) and
SIRT2 deacetylate H3K56 acetylation. The histone chaperones ASF1A
(609189) in humans and Asf1 in Drosophila are required for acetylation
of H3K56 in vivo, whereas the histone chaperone CAF1 (see 601245) in
humans and Caf1 in Drosophila are required for the incorporation of
histones bearing this mark into chromatin. Das et al. (2009) showed
that, in response to DNA damage, histones bearing acetylated K56 are
assembled into chromatin in Drosophila and human cells, forming foci
that colocalize with sites of DNA repair. Furthermore, acetylation of
H3K56 is increased in multiple types of cancer, correlating with
increased levels of ASF1A in these tumors. Das et al. (2009) concluded
that their identification of multiple proteins regulating the levels of
H3K56 acetylation in metazoans will allow future studies of this
critical and unique histone modification that couples chromatin assembly
to DNA synthesis, cell proliferation, and cancer.
Narayan et al. (2012) showed that the NAD-dependent deacetylase SIRT2
binds constitutively to RIP3 (605817) and the deletion or knockdown of
SIRT2 prevents formation of the RIP1 (603453)-RIP3 complex in mice.
Furthermore, genetic or pharmacologic inhibition of SIRT2 blocks
cellular necrosis induced by TNF-alpha (191160). Narayan et al. (2012)
further demonstrated that RIP1 is a critical target of SIRT2-dependent
deacetylation. Using gain- and loss-of-function mutants, Narayan et al.
(2012) demonstrated that acetylation of RIP1 lysine-530 modulates
RIP1-RIP3 complex formation in TNF-alpha-stimulated necrosis. In a
setting of ischemia-reperfusion injury, RIP1 was deacetylated in a
SIRT2-dependent fashion. Furthermore, the hearts of Sirt2-null mice, or
wildtype mice treated with a specific pharmacologic inhibitor of SIRT2,
showed marked protection from ischemic injury. Narayan et al. (2012)
concluded that, taken together, their results implicated SIRT2 as an
important regulator of programmed necrosis and indicated that inhibitors
of this deacetylase may constitute a novel approach to protect against
necrotic injuries, including ischemic stroke and myocardial infarction.
By infecting HeLa cells or mice with Listeria monocytogenes, Eskandarian
et al. (2013) found that histone H3 (see 602820) was deacetylated at
lys18 (K18), but not at K9 or K14. H3K18 deacetylation was mediated by
SIRT2, which was targeted to the nucleus and associated with chromatin
upon infection. Screening infection-defective Listeria mutants showed
that induction of deacetylation required another virulence factor, InlB,
in addition to the listeriolysin virulence factor. InlB interacted with
the surface MET receptor (MET; 164860). Alternatively, the MET ligand,
HGF (142409), but not EGF (131530), induced H3K18 deacetylation through
PI3K (see 601232)/AKT (164730) signaling. Transcriptome analysis
revealed that L. monocytogenes infection induced SIRT2-dependent
modulation of host gene expression with imposition of H3K18
deacetylation at transcriptional start sites, resulting in gene
repression. Treating cells with small interfering RNA to SIRT2, but not
to other SIRTs, showed that SIRT2 was critical for infection with L.
monocytogenes. Eskandarian et al. (2013) concluded that L. monocytogenes
hijacks the host histone deacetylase, SIRT2, to impose a transcriptional
program on the host through activation of the PI3K/AKT signaling
cascade.
MAPPING
Frye (1999) stated that EST sequence fragments of the SIRT2 cDNA have
been mapped to chromosome 19q.
*FIELD* RF
1. Afshar, G.; Murnane, J. P.: Characterization of a human gene with
sequence homology to Saccharomyces cerevisiae SIR2. Gene 234: 161-168,
1999.
2. Aguilaniu, H.; Gustafsson, L.; Rigoulet, M.; Nystrom, T.: Asymmetric
inheritance of oxidatively damaged proteins during cytokinesis. Science 299:
1751-1753, 2003.
3. Das, C.; Lucia, M. S.; Hansen, K. C.; Tyler, J. K.: CBP/p300-mediated
acetylation of histone H3 on lysine56. Nature 459: 113-117, 2009.
Note: Erratum: Nature 460: 1164 only, 2009.
4. Dryden, S. C.; Nahhas, F. A.; Nowak, J. E.; Goustin, A.-S.; Tainsky,
M. A.: Role for human SIRT2 NAD-dependent deacetylase activity in
control of mitotic exit in the cell cycle. Molec. Cell Biol. 23:
3173-3185, 2003.
5. Eskandarian, H. A.; Impens, F.; Nahori, M.-A.; Soubigou, G.; Coppee,
J.-Y.; Cossart, P.; Hamon, M. A.: A role for SIRT2-dependent histone
H3K18 deacetylation in bacterial infection. Science. 341: 525 only,
2013. Note: Full Article Online.
6. Frye, R. A.: Characterization of five human cDNAs with homology
to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD
and may have protein ADP-ribosyltransferase activity. Biochem. Biophys.
Res. Commun. 260: 273-279, 1999.
7. Narayan, N.; Lee, I. H.; Borenstein, R.; Sun, J.; Wong, R.; Tong,
G.; Fergusson, M. M.; Liu, J.; Rovira, I. I.; Cheng, H.-L.; Wang,
G.; Gucek, M.; Lombard, D.; Alt, F. W.; Sack, M. N.; Murphy, E.; Cao,
L.; Finkel, T.: The NAD-dependent deacetylase SIRT2 is required for
programmed necrosis. Nature 492: 199-204, 2012.
8. North, B. J.; Marshall, B. L.; Borra, M. T.; Denu, J. M.; Verdin,
E.: The human Sir2 ortholog, SIRT2, is an NAD(+)-dependent tubulin
deacetylase. Molec. Cell 11: 437-444, 2003.
9. Outeiro, T. F.; Kontopoulous, E.; Altmann, S. M.; Kufareva, I.;
Strathearn, K. E.; Amore, A. M.; Volk, C. B.; Maxwell, M. M.; Rochet,
J.-C.; McLean, P. J.; Young, A. B.; Abagyan, R.; Feany, M. B.; Hyman,
B. T.; Kazantsev, A. G.: Sirtuin 2 inhibitors rescue alpha-synuclein-mediated
toxicity in models of Parkinson's disease. Science 317: 516-519,
2007.
10. Rogina, B.; Helfand, S. L.; Frankel, S.: Longevity regulation
by Drosophila Rpd3 deacetylase and caloric restriction. Science 298:
1745 only, 2002.
11. Sherman, J. M.; Stone, E. M.; Freeman-Cook, L. L.; Brachmann,
C. B.; Boeke, J. D.; Pillus, L.: The conserved core of a human SIR2
homologue functions in yeast silencing. Molec. Biol. Cell 10: 3045-3059,
1999.
12. Shore, D.; Squire, M.; Nasmyth, K. A.: Characterization of two
genes required for the position-effect control of yeast mating-type
genes. EMBO J. 3: 2817-2823, 1984.
13. Tanny, J. C.; Dowd, G. J.; Huang, J.; Hilz, H.; Moazed, D.: An
enzymatic activity in the yeast Sir2 protein that is essential for
gene silencing. Cell 99: 735-745, 1999.
*FIELD* CN
Paul J. Converse - updated: 10/14/2013
Ada Hamosh - updated: 1/29/2013
Ada Hamosh - updated: 9/9/2009
Ada Hamosh - updated: 5/19/2009
Ada Hamosh - updated: 8/15/2007
Patricia A. Hartz - updated: 8/13/2007
Patricia A. Hartz - updated: 12/12/2005
Stylianos E. Antonarakis - updated: 4/21/2003
Ada Hamosh - updated: 4/3/2003
Ada Hamosh - updated: 2/13/2003
*FIELD* CD
Stylianos E. Antonarakis: 1/31/2000
*FIELD* ED
mgross: 10/14/2013
alopez: 1/31/2013
terry: 1/29/2013
carol: 4/5/2010
terry: 9/9/2009
alopez: 6/4/2009
terry: 5/19/2009
carol: 8/15/2007
terry: 8/13/2007
alopez: 7/23/2007
wwang: 12/12/2005
mgross: 4/21/2003
alopez: 4/8/2003
terry: 4/3/2003
alopez: 2/19/2003
terry: 2/13/2003
cwells: 11/19/2002
terry: 11/15/2002
carol: 3/23/2001
alopez: 2/21/2000
mgross: 1/31/2000
*RECORD*
*FIELD* NO
604480
*FIELD* TI
*604480 SIRTUIN 2; SIRT2
;;SIR2, S. CEREVISIAE, HOMOLOG-LIKE 2; SIR2L2;;
SIR2L
*FIELD* TX
read more
CLONING
The yeast Sir2 (silent information regulator-2) protein (Shore et al.,
1984) regulates epigenetic gene silencing and, as a possible antiaging
effect, suppresses recombination of rDNA. Studies involving cobB, a
bacterial Sir2-like gene, have suggested that Sir2 may encode a pyridine
nucleotide transferase. By in silico and PCR-cloning techniques, Frye
(1999) obtained cDNA sequences encoding 5 human Sir2-like genes, which
they called sirtuin-1 to -5 (SIRT1 to SIRT5). The SIRT1 (604479)
sequence has the closest homology to the S. cerevisiae Sir2 protein,
while SIRT4 (604482) and SIRT5 (604483) more closely resemble
prokaryotic sirtuin sequences. PCR analysis showed that the 5 human
sirtuins are widely expressed in fetal and adult tissues.
Afshar and Murnane (1999) sequenced a full-length SIRT2 (SIR2L) EST
clone. The deduced 352-amino acid protein has a calculated molecular
mass of 39.5 kD. It has 2 potential leucine zipper motifs, 6 possible
N-myristoylation sites, and several potential protein kinase C (see
PRKCA, 176960) phosphorylation sites. Northern blot analysis detected
variable expression of a 2.1-kb transcript in all tissues examined, with
higher expression in heart, brain, and skeletal muscle, and lower
expression in placenta and lung. Fluorescence-tagged SIRT2 localized
primarily in the cytoplasm of transfected human fibroblasts and a tumor
cell line.
GENE FUNCTION
Frye (1999) found that recombinant human SIRT2 was able to cause
radioactivity to be transferred from (32P)NAD to bovine serum albumin
(BSA). When a conserved histidine within SIRT2 was converted to
tyrosine, the mutant recombinant protein was unable to transfer
radioactivity from (32P)NAD to BSA. These results suggested that the
sirtuins may function via mono-ADP-ribosylation of proteins.
Tanny et al. (1999) showed that the yeast Sir2 protein can transfer
labeled phosphate from nicotinamide adenine dinucleotide to itself and
histones in vitro. A modified form of Sir2, which results from its
automodification activity, was specifically recognized by
anti-mono-ADP-ribose antibodies, suggesting that Sir2 is an
ADP-ribosyltransferase. Mutation of a phylogenetically invariant
histidine (his364 to tyr) in Sir2 abolished both its enzymatic activity
in vitro and its silencing functions in vivo. However, the mutant
protein was associated with chromatin and other silencing factors in a
manner similar to wildtype Sir2. These findings suggested that Sir2
contains an ADP-ribosyltransferase activity that is essential for its
silencing function.
Rogina et al. (2002) found that under 2 life-extending conditions, Rpd3
(601241) mutants fed normal food and wildtype flies fed low calorie
food, Sir2 expression was increased 2-fold.
Carbonylated proteins, which are a sign of irreversible oxidative
damage, were visualized in single cells of S. cerevisiae, revealing that
they accumulate with replicative age. Aguilaniu et al. (2003) showed the
carbonylated proteins were not inherited by daughter cells during
cytokinesis. Mother cells of a yeast strain lacking the Sir2 gene, a
life-span determinant, failed to retain oxidatively damaged proteins
during cytokinesis. Aguilaniu et al. (2003) concluded that a genetically
determined, SIR2-dependent asymmetric inheritance of oxidatively damaged
proteins may contribute to free-radical defense and the fitness of
newborn cells.
North et al. (2003) reported that SIRT2 is a predominantly cytoplasmic
protein that colocalizes with microtubules. SIRT2 was found to
deacetylate lys40 of alpha-tubulin (602530) both in vitro and in vivo.
Knockdown of SIRT2 via small interfering RNA resulted in tubulin
hyperacetylation. SIRT2 colocalized and interacted in vivo with HDAC6
(300272), another tubulin deacetylase. Enzymatic analysis of recombinant
SIRT2 in comparison to a yeast homolog of Sir2 protein showed a striking
preference of SIRT2 for acetylated tubulin peptide as a substrate
relative to acetylated histone H3 peptide. These observations
established SIRT2 as a bona fide tubulin deacetylase.
By Western blot analysis of a human osteosarcoma cell line, Dryden et
al. (2003) resolved SIRT2 into isoforms of about 48 kD and above that
differed in their degree of phosphorylation. Using synchronized cells,
they found that the hyperphosphorylated forms of SIRT2 were confined to
the M phase of the cell cycle, coincident with the G2/M transition, and
maintained throughout the M phase. Overexpression of SIRT2 resulted in
increased NAD-dependent deacetylase activity and delayed cell cycle
progression through mitosis. Overexpression of CDC14B (603505), but not
CDC14A (603504) or a CDC14B mutant lacking phosphatase activity, led to
the loss of hyperphosphorylated SIRT2. In the presence of other mitotic
regulators, such as B-type cyclins (see 123836), SIRT2 became
ubiquitinated and was degraded via the 26S proteasome pathway. Dryden et
al. (2003) concluded that SIRT2 is a regulator of mitotic progression
that acts downstream from CDC14B in a pathway regulating mitotic exit or
subsequent cytokinesis.
By mutation analysis, Sherman et al. (1999) found that the conserved
core domain of SIR2 proteins, which includes 2 sequence motifs and 4
cysteines of a putative zinc finger, is essential for gene silencing.
Chimeras between yeast and human SIR2 homologs showed that the human
core domain can substitute for that of yeast, confirming that the
conserved core is a silencing domain.
Outeiro et al. (2007) identified a potent inhibitor of SIRT2 and found
that inhibition of SIRT2 rescued alpha-synuclein (163890) toxicity and
modified inclusion morphology in a cellular model of Parkinson disease
(168600). Genetic inhibition of SIRT2 via small interfering RNA
similarly rescued alpha-synuclein toxicity. The inhibitors protected
against dopaminergic cell death both in vitro and in a Drosophila model
of Parkinson disease. Outeiro et al. (2007) concluded that their results
suggest a link between neurodegeneration and aging.
Das et al. (2009) demonstrated that the histone acetyltransferase CBP
(600140) in flies, and CBP and p300 in humans, acetylate histone H3 on
lys56 (H3K56), whereas Drosophila sir2 and human SIRT1 (604479) and
SIRT2 deacetylate H3K56 acetylation. The histone chaperones ASF1A
(609189) in humans and Asf1 in Drosophila are required for acetylation
of H3K56 in vivo, whereas the histone chaperone CAF1 (see 601245) in
humans and Caf1 in Drosophila are required for the incorporation of
histones bearing this mark into chromatin. Das et al. (2009) showed
that, in response to DNA damage, histones bearing acetylated K56 are
assembled into chromatin in Drosophila and human cells, forming foci
that colocalize with sites of DNA repair. Furthermore, acetylation of
H3K56 is increased in multiple types of cancer, correlating with
increased levels of ASF1A in these tumors. Das et al. (2009) concluded
that their identification of multiple proteins regulating the levels of
H3K56 acetylation in metazoans will allow future studies of this
critical and unique histone modification that couples chromatin assembly
to DNA synthesis, cell proliferation, and cancer.
Narayan et al. (2012) showed that the NAD-dependent deacetylase SIRT2
binds constitutively to RIP3 (605817) and the deletion or knockdown of
SIRT2 prevents formation of the RIP1 (603453)-RIP3 complex in mice.
Furthermore, genetic or pharmacologic inhibition of SIRT2 blocks
cellular necrosis induced by TNF-alpha (191160). Narayan et al. (2012)
further demonstrated that RIP1 is a critical target of SIRT2-dependent
deacetylation. Using gain- and loss-of-function mutants, Narayan et al.
(2012) demonstrated that acetylation of RIP1 lysine-530 modulates
RIP1-RIP3 complex formation in TNF-alpha-stimulated necrosis. In a
setting of ischemia-reperfusion injury, RIP1 was deacetylated in a
SIRT2-dependent fashion. Furthermore, the hearts of Sirt2-null mice, or
wildtype mice treated with a specific pharmacologic inhibitor of SIRT2,
showed marked protection from ischemic injury. Narayan et al. (2012)
concluded that, taken together, their results implicated SIRT2 as an
important regulator of programmed necrosis and indicated that inhibitors
of this deacetylase may constitute a novel approach to protect against
necrotic injuries, including ischemic stroke and myocardial infarction.
By infecting HeLa cells or mice with Listeria monocytogenes, Eskandarian
et al. (2013) found that histone H3 (see 602820) was deacetylated at
lys18 (K18), but not at K9 or K14. H3K18 deacetylation was mediated by
SIRT2, which was targeted to the nucleus and associated with chromatin
upon infection. Screening infection-defective Listeria mutants showed
that induction of deacetylation required another virulence factor, InlB,
in addition to the listeriolysin virulence factor. InlB interacted with
the surface MET receptor (MET; 164860). Alternatively, the MET ligand,
HGF (142409), but not EGF (131530), induced H3K18 deacetylation through
PI3K (see 601232)/AKT (164730) signaling. Transcriptome analysis
revealed that L. monocytogenes infection induced SIRT2-dependent
modulation of host gene expression with imposition of H3K18
deacetylation at transcriptional start sites, resulting in gene
repression. Treating cells with small interfering RNA to SIRT2, but not
to other SIRTs, showed that SIRT2 was critical for infection with L.
monocytogenes. Eskandarian et al. (2013) concluded that L. monocytogenes
hijacks the host histone deacetylase, SIRT2, to impose a transcriptional
program on the host through activation of the PI3K/AKT signaling
cascade.
MAPPING
Frye (1999) stated that EST sequence fragments of the SIRT2 cDNA have
been mapped to chromosome 19q.
*FIELD* RF
1. Afshar, G.; Murnane, J. P.: Characterization of a human gene with
sequence homology to Saccharomyces cerevisiae SIR2. Gene 234: 161-168,
1999.
2. Aguilaniu, H.; Gustafsson, L.; Rigoulet, M.; Nystrom, T.: Asymmetric
inheritance of oxidatively damaged proteins during cytokinesis. Science 299:
1751-1753, 2003.
3. Das, C.; Lucia, M. S.; Hansen, K. C.; Tyler, J. K.: CBP/p300-mediated
acetylation of histone H3 on lysine56. Nature 459: 113-117, 2009.
Note: Erratum: Nature 460: 1164 only, 2009.
4. Dryden, S. C.; Nahhas, F. A.; Nowak, J. E.; Goustin, A.-S.; Tainsky,
M. A.: Role for human SIRT2 NAD-dependent deacetylase activity in
control of mitotic exit in the cell cycle. Molec. Cell Biol. 23:
3173-3185, 2003.
5. Eskandarian, H. A.; Impens, F.; Nahori, M.-A.; Soubigou, G.; Coppee,
J.-Y.; Cossart, P.; Hamon, M. A.: A role for SIRT2-dependent histone
H3K18 deacetylation in bacterial infection. Science. 341: 525 only,
2013. Note: Full Article Online.
6. Frye, R. A.: Characterization of five human cDNAs with homology
to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD
and may have protein ADP-ribosyltransferase activity. Biochem. Biophys.
Res. Commun. 260: 273-279, 1999.
7. Narayan, N.; Lee, I. H.; Borenstein, R.; Sun, J.; Wong, R.; Tong,
G.; Fergusson, M. M.; Liu, J.; Rovira, I. I.; Cheng, H.-L.; Wang,
G.; Gucek, M.; Lombard, D.; Alt, F. W.; Sack, M. N.; Murphy, E.; Cao,
L.; Finkel, T.: The NAD-dependent deacetylase SIRT2 is required for
programmed necrosis. Nature 492: 199-204, 2012.
8. North, B. J.; Marshall, B. L.; Borra, M. T.; Denu, J. M.; Verdin,
E.: The human Sir2 ortholog, SIRT2, is an NAD(+)-dependent tubulin
deacetylase. Molec. Cell 11: 437-444, 2003.
9. Outeiro, T. F.; Kontopoulous, E.; Altmann, S. M.; Kufareva, I.;
Strathearn, K. E.; Amore, A. M.; Volk, C. B.; Maxwell, M. M.; Rochet,
J.-C.; McLean, P. J.; Young, A. B.; Abagyan, R.; Feany, M. B.; Hyman,
B. T.; Kazantsev, A. G.: Sirtuin 2 inhibitors rescue alpha-synuclein-mediated
toxicity in models of Parkinson's disease. Science 317: 516-519,
2007.
10. Rogina, B.; Helfand, S. L.; Frankel, S.: Longevity regulation
by Drosophila Rpd3 deacetylase and caloric restriction. Science 298:
1745 only, 2002.
11. Sherman, J. M.; Stone, E. M.; Freeman-Cook, L. L.; Brachmann,
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*FIELD* CN
Paul J. Converse - updated: 10/14/2013
Ada Hamosh - updated: 1/29/2013
Ada Hamosh - updated: 9/9/2009
Ada Hamosh - updated: 5/19/2009
Ada Hamosh - updated: 8/15/2007
Patricia A. Hartz - updated: 8/13/2007
Patricia A. Hartz - updated: 12/12/2005
Stylianos E. Antonarakis - updated: 4/21/2003
Ada Hamosh - updated: 4/3/2003
Ada Hamosh - updated: 2/13/2003
*FIELD* CD
Stylianos E. Antonarakis: 1/31/2000
*FIELD* ED
mgross: 10/14/2013
alopez: 1/31/2013
terry: 1/29/2013
carol: 4/5/2010
terry: 9/9/2009
alopez: 6/4/2009
terry: 5/19/2009
carol: 8/15/2007
terry: 8/13/2007
alopez: 7/23/2007
wwang: 12/12/2005
mgross: 4/21/2003
alopez: 4/8/2003
terry: 4/3/2003
alopez: 2/19/2003
terry: 2/13/2003
cwells: 11/19/2002
terry: 11/15/2002
carol: 3/23/2001
alopez: 2/21/2000
mgross: 1/31/2000