SIR6_HUMAN
ID SIR6_HUMAN Reviewed; 355 AA.
AC Q8N6T7; B2RCD0; O75291; Q6IAF5; Q6PK99; Q8NCD2; Q9BSI5; Q9BWP3; Q9NRC7;
AC Q9UQD1;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2003, sequence version 2.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=NAD-dependent protein deacylase sirtuin-6 {ECO:0000305};
DE EC=2.3.1.- {ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:29555651};
DE AltName: Full=NAD-dependent protein deacetylase sirtuin-6 {ECO:0000305};
DE EC=2.3.1.286 {ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:27043296, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:33067423, ECO:0000269|PubMed:33122195};
DE AltName: Full=Protein mono-ADP-ribosyltransferase sirtuin-6 {ECO:0000305};
DE EC=2.4.2.- {ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:27568560};
DE AltName: Full=Regulatory protein SIR2 homolog 6 {ECO:0000303|PubMed:10873683};
DE Short=hSIRT6 {ECO:0000303|PubMed:33122195};
DE AltName: Full=SIR2-like protein 6;
GN Name=SIRT6 {ECO:0000303|PubMed:10873683, ECO:0000312|HGNC:HGNC:14934};
GN Synonyms=SIR2L6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Spleen;
RX PubMed=10873683; DOI=10.1006/bbrc.2000.3000;
RA Frye R.A.;
RT "Phylogenetic classification of prokaryotic and eukaryotic Sir-2 like
RT proteins.";
RL Biochem. Biophys. Res. Commun. 273:793-798(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ASN-46.
RC TISSUE=Heart, and Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ASN-46.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ASN-46.
RC TISSUE=Blood, Eye, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
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 [8]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF HIS-133, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18337721; DOI=10.1038/nature06736;
RA Michishita E., McCord R.A., Berber E., Kioi M., Padilla-Nash H., Damian M.,
RA Cheung P., Kusumoto R., Kawahara T.L.A., Barrett J.C., Chang H.Y.,
RA Bohr V.A., Ried T., Gozani O., Chua K.F.;
RT "SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric
RT chromatin.";
RL Nature 452:492-496(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-303, AND IDENTIFICATION BY
RP 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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP FUNCTION, INTERACTION WITH RELA, AND SUBCELLULAR LOCATION.
RX PubMed=19135889; DOI=10.1016/j.cell.2008.10.052;
RA Kawahara T.L.A., Michishita E., Adler A.S., Damian M., Berber E., Lin M.,
RA McCord R.A., Ongaigui K.C.L., Boxer L.D., Chang H.Y., Chua K.F.;
RT "SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene
RT expression and organismal life span.";
RL Cell 136:62-74(2009).
RN [12]
RP FUNCTION.
RX PubMed=19625767; DOI=10.4161/cc.8.16.9367;
RA Michishita E., McCord R.A., Boxer L.D., Barber M.F., Hong T., Gozani O.,
RA Chua K.F.;
RT "Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by
RT human SIRT6.";
RL Cell Cycle 8:2664-2666(2009).
RN [13]
RP RETRACTED PAPER.
RX PubMed=20829486; DOI=10.1126/science.1192049;
RA Kaidi A., Weinert B.T., Choudhary C., Jackson S.P.;
RT "Human SIRT6 promotes DNA end resection through CtIP deacetylation.";
RL Science 329:1348-1353(2010).
RN [14]
RP RETRACTION NOTICE OF PUBMED:20829486.
RX PubMed=30975768; DOI=10.1126/science.aax4558;
RA Kaidi A., Weinert B.T., Choudhary C., Jackson S.P.;
RL Science 364:247-247(2019).
RN [15]
RP FUNCTION.
RX PubMed=21847107; DOI=10.1038/ncomms1443;
RA Tennen R.I., Bua D.J., Wright W.E., Chua K.F.;
RT "SIRT6 is required for maintenance of telomere position effect in human
RT cells.";
RL Nat. Commun. 2:433-433(2011).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP SER-56; GLY-60 AND ARG-65.
RX PubMed=21680843; DOI=10.1126/science.1202723;
RA Mao Z., Hine C., Tian X., Van Meter M., Au M., Vaidya A., Seluanov A.,
RA Gorbunova V.;
RT "SIRT6 promotes DNA repair under stress by activating PARP1.";
RL Science 332:1443-1446(2011).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP FUNCTION, AND INDUCTION.
RX PubMed=23217706; DOI=10.1016/j.cell.2012.10.047;
RA Sebastian C., Zwaans B.M., Silberman D.M., Gymrek M., Goren A., Zhong L.,
RA Ram O., Truelove J., Guimaraes A.R., Toiber D., Cosentino C.,
RA Greenson J.K., MacDonald A.I., McGlynn L., Maxwell F., Edwards J.,
RA Giacosa S., Guccione E., Weissleder R., Bernstein B.E., Regev A.,
RA Shiels P.G., Lombard D.B., Mostoslavsky R.;
RT "The histone deacetylase SIRT6 is a tumor suppressor that controls cancer
RT metabolism.";
RL Cell 151:1185-1199(2012).
RN [19]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF TYR-133.
RX PubMed=23142079; DOI=10.1016/j.molcel.2012.09.030;
RA Dominy J.E. Jr., Lee Y., Jedrychowski M.P., Chim H., Jurczak M.J.,
RA Camporez J.P., Ruan H.B., Feldman J., Pierce K., Mostoslavsky R.,
RA Denu J.M., Clish C.B., Yang X., Shulman G.I., Gygi S.P., Puigserver P.;
RT "The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses
RT hepatic gluconeogenesis.";
RL Mol. Cell 48:900-913(2012).
RN [20]
RP FUNCTION, AND MUTAGENESIS OF SER-56; GLY-60 AND ARG-65.
RX PubMed=22753495; DOI=10.1073/pnas.1200583109;
RA Mao Z., Tian X., Van Meter M., Ke Z., Gorbunova V., Seluanov A.;
RT "Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair
RT during replicative senescence.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:11800-11805(2012).
RN [21]
RP FUNCTION.
RX PubMed=24012758; DOI=10.1016/j.celrep.2013.08.006;
RA Elhanati S., Kanfi Y., Varvak A., Roichman A., Carmel-Gross I., Barth S.,
RA Gibor G., Cohen H.Y.;
RT "Multiple regulatory layers of SREBP1/2 by SIRT6.";
RL Cell Rep. 4:905-912(2013).
RN [22]
RP FUNCTION.
RX PubMed=23653361; DOI=10.1074/jbc.m112.405928;
RA Sharma A., Diecke S., Zhang W.Y., Lan F., He C., Mordwinkin N.M.,
RA Chua K.F., Wu J.C.;
RT "The role of SIRT6 protein in aging and reprogramming of human induced
RT pluripotent stem cells.";
RL J. Biol. Chem. 288:18439-18447(2013).
RN [23]
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=24052263; DOI=10.1074/jbc.c113.511261;
RA Feldman J.L., Baeza J., Denu J.M.;
RT "Activation of the protein deacetylase SIRT6 by long-chain fatty acids and
RT widespread deacylation by mammalian sirtuins.";
RL J. Biol. Chem. 288:31350-31356(2013).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10; SER-303 AND SER-330, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SMARCA5, AND MUTAGENESIS
RP OF HIS-133.
RX PubMed=23911928; DOI=10.1016/j.molcel.2013.06.018;
RA Toiber D., Erdel F., Bouazoune K., Silberman D.M., Zhong L., Mulligan P.,
RA Sebastian C., Cosentino C., Martinez-Pastor B., Giacosa S., D'Urso A.,
RA Naeaer A.M., Kingston R., Rippe K., Mostoslavsky R.;
RT "SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability
RT through chromatin remodeling.";
RL Mol. Cell 51:454-468(2013).
RN [26]
RP UBIQUITINATION AT LYS-170, AND MUTAGENESIS OF LYS-170.
RX PubMed=24043303; DOI=10.1128/mcb.00480-13;
RA Ronnebaum S.M., Wu Y., McDonough H., Patterson C.;
RT "The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical
RT ubiquitination.";
RL Mol. Cell. Biol. 33:4461-4472(2013).
RN [27]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, ACTIVE SITE, AND
RP MUTAGENESIS OF HIS-133.
RX PubMed=23892288; DOI=10.1093/nar/gkt642;
RA Gil R., Barth S., Kanfi Y., Cohen H.Y.;
RT "SIRT6 exhibits nucleosome-dependent deacetylase activity.";
RL Nucleic Acids Res. 41:8537-8545(2013).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-294, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [29]
RP POLYMORPHISM.
RX PubMed=25541994; DOI=10.1371/journal.pone.0115616;
RA TenNapel M.J., Lynch C.F., Burns T.L., Wallace R., Smith B.J., Button A.,
RA Domann F.E.;
RT "SIRT6 minor allele genotype is associated with >5-year decrease in
RT lifespan in an aged cohort.";
RL PLoS ONE 9:e115616-e115616(2014).
RN [30]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=25009184; DOI=10.1073/pnas.1411026111;
RA Zhang P., Tu B., Wang H., Cao Z., Tang M., Zhang C., Gu B., Li Z., Wang L.,
RA Yang Y., Zhao Y., Wang H., Luo J., Deng C.X., Gao B., Roeder R.G.,
RA Zhu W.G.;
RT "Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by
RT promoting FoxO1 nuclear exclusion.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:10684-10689(2014).
RN [31]
RP FUNCTION.
RX PubMed=25915124; DOI=10.1038/ncb3147;
RA Etchegaray J.P., Chavez L., Huang Y., Ross K.N., Choi J.,
RA Martinez-Pastor B., Walsh R.M., Sommer C.A., Lienhard M., Gladden A.,
RA Kugel S., Silberman D.M., Ramaswamy S., Mostoslavsky G., Hochedlinger K.,
RA Goren A., Rao A., Mostoslavsky R.;
RT "The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-
RT mediated production of 5-hydroxymethylcytosine.";
RL Nat. Cell Biol. 17:545-557(2015).
RN [32]
RP INDUCTION.
RX PubMed=26748705; DOI=10.1016/j.celrep.2015.12.023;
RA Elhanati S., Ben-Hamo R., Kanfi Y., Varvak A., Glazz R., Lerrer B.,
RA Efroni S., Cohen H.Y.;
RT "Reciprocal regulation between SIRT6 and miR-122 controls liver metabolism
RT and predicts hepatocarcinoma prognosis.";
RL Cell Rep. 14:234-242(2016).
RN [33]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, PHOSPHORYLATION AT
RP SER-10, AND MUTAGENESIS OF SER-10; THR-294; SER-303; SER-330 AND SER-338.
RX PubMed=27568560; DOI=10.1016/j.celrep.2016.08.006;
RA Van Meter M., Simon M., Tombline G., May A., Morello T.D., Hubbard B.P.,
RA Bredbenner K., Park R., Sinclair D.A., Bohr V.A., Gorbunova V.,
RA Seluanov A.;
RT "JNK phosphorylates SIRT6 to stimulate DNA double-strand break repair in
RT response to oxidative stress by recruiting PARP1 to DNA Breaks.";
RL Cell Rep. 16:2641-2650(2016).
RN [34]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND
RP RNA-BINDING.
RX PubMed=27912097; DOI=10.1016/j.molcel.2016.10.039;
RA Jain A.K., Xi Y., McCarthy R., Allton K., Akdemir K.C., Patel L.R.,
RA Aronow B., Lin C., Li W., Yang L., Barton M.C.;
RT "LncPRESS1 is a p53-regulated lncRNA that safeguards pluripotency by
RT disrupting SIRT6-mediated de-acetylation of histone H3K56.";
RL Mol. Cell 64:967-981(2016).
RN [35]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF SER-56;
RP GLY-60; ARG-65 AND HIS-133.
RX PubMed=27322069; DOI=10.1038/nchembio.2106;
RA Zhang X., Khan S., Jiang H., Antonyak M.A., Chen X., Spiegelman N.A.,
RA Shrimp J.H., Cerione R.A., Lin H.;
RT "Identifying the functional contribution of the defatty-acylase activity of
RT SIRT6.";
RL Nat. Chem. Biol. 12:614-620(2016).
RN [36]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF HIS-133.
RX PubMed=27043296; DOI=10.1038/nsmb.3202;
RA Tasselli L., Xi Y., Zheng W., Tennen R.I., Odrowaz Z., Simeoni F., Li W.,
RA Chua K.F.;
RT "SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic
RT errors and cellular senescence.";
RL Nat. Struct. Mol. Biol. 23:434-440(2016).
RN [37]
RP FUNCTION, SUBCELLULAR LOCATION, SUMOYLATION, AND MUTAGENESIS OF
RP 296-LYS--LYS-300; LYS-316 AND LYS-332.
RX PubMed=26898756; DOI=10.1038/onc.2016.24;
RA Cai J., Zuo Y., Wang T., Cao Y., Cai R., Chen F.L., Cheng J., Mu J.;
RT "A crucial role of SUMOylation in modulating Sirt6 deacetylation of H3 at
RT lysine 56 and its tumor suppressive activity.";
RL Oncogene 35:4949-4956(2016).
RN [38]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF TYR-133.
RX PubMed=26787900; DOI=10.1073/pnas.1520045113;
RA Bhardwaj A., Das S.;
RT "SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic
RT functions.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:E538-E547(2016).
RN [39]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-133.
RX PubMed=29474172; DOI=10.7554/elife.32127;
RA Ghosh S., Wong S.K., Jiang Z., Liu B., Wang Y., Hao Q., Gorbunova V.,
RA Liu X., Zhou Z.;
RT "Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-
RT deficient mice.";
RL Elife 7:0-0(2018).
RN [40]
RP FUNCTION, ACTIVE SITE, AND MUTAGENESIS OF GLY-60 AND HIS-133.
RX PubMed=28406396; DOI=10.7554/elife.25158;
RA Zhang X., Spiegelman N.A., Nelson O.D., Jing H., Lin H.;
RT "SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation.";
RL Elife 6:0-0(2017).
RN [41]
RP FUNCTION.
RX PubMed=27180906; DOI=10.1016/j.cell.2016.04.033;
RA Kugel S., Sebastian C., Fitamant J., Ross K.N., Saha S.K., Jain E.,
RA Gladden A., Arora K.S., Kato Y., Rivera M.N., Ramaswamy S., Sadreyev R.I.,
RA Goren A., Deshpande V., Bardeesy N., Mostoslavsky R.;
RT "SIRT6 suppresses pancreatic cancer through control of Lin28b.";
RL Cell 165:1401-1415(2016).
RN [42]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, MUTAGENESIS OF ALA-13 AND HIS-133,
RP AND CHARACTERIZATION OF VARIANTS HIS-63 AND TYR-63.
RX PubMed=31995034; DOI=10.7554/elife.51636;
RA Onn L., Portillo M., Ilic S., Cleitman G., Stein D., Kaluski S., Shirat I.,
RA Slobodnik Z., Einav M., Erdel F., Akabayov B., Toiber D.;
RT "SIRT6 is a DNA double-strand break sensor.";
RL Elife 9:0-0(2020).
RN [43]
RP FUNCTION, SUBCELLULAR LOCATION, ACETYLATION AT LYS-33, AND MUTAGENESIS OF
RP LYS-15; LYS-17; LYS-33 AND HIS-133.
RX PubMed=32538779; DOI=10.7554/elife.55828;
RA Meng F., Qian M., Peng B., Peng L., Wang X., Zheng K., Liu Z., Tang X.,
RA Zhang S., Sun S., Cao X., Pang Q., Zhao B., Ma W., Songyang Z., Xu B.,
RA Zhu W.G., Xu X., Liu B.;
RT "Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates
RT the DNA damage response and repair in humans and mice.";
RL Elife 9:0-0(2020).
RN [44]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=33122195; DOI=10.1074/jbc.ra120.014883;
RA Carreno M., Bresque M., Machado M.R., Santos L., Duran R., Vitturi D.A.,
RA Escande C., Denicola A.;
RT "Nitro-fatty acids as activators of hSIRT6 deacetylase activity.";
RL J. Biol. Chem. 295:18355-18366(2020).
RN [45]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, DOMAIN, DNA-BINDING, AND
RP MUTAGENESIS OF SER-45 AND 206-ASN--ASP-208.
RX PubMed=33067423; DOI=10.1038/s41467-020-19018-y;
RA Liu W.H., Zheng J., Feldman J.L., Klein M.A., Kuznetsov V.I.,
RA Peterson C.L., Griffin P.R., Denu J.M.;
RT "Multivalent interactions drive nucleosome binding and efficient chromatin
RT deacetylation by SIRT6.";
RL Nat. Commun. 11:5244-5244(2020).
RN [46]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP SER-56 AND HIS-133.
RX PubMed=32789493; DOI=10.1093/nar/gkaa661;
RA Geng A., Tang H., Huang J., Qian Z., Qin N., Yao Y., Xu Z., Chen H.,
RA Lan L., Xie H., Zhang J., Jiang Y., Mao Z.;
RT "The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by
RT targeting DDB2.";
RL Nucleic Acids Res. 48:9181-9194(2020).
RN [47] {ECO:0007744|PDB:3K35, ECO:0007744|PDB:3PKI, ECO:0007744|PDB:3PKJ}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 2-318 IN COMPLEX WITH ZINC AND
RP ADP-RIBOSE, FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=21362626; DOI=10.1074/jbc.m111.218990;
RA Pan P.W., Feldman J.L., Devries M.K., Dong A., Edwards A.M., Denu J.M.;
RT "Structure and biochemical functions of SIRT6.";
RL J. Biol. Chem. 286:14575-14587(2011).
RN [48] {ECO:0007744|PDB:3ZG6}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 1-296 IN COMPLEX WITH ZINC,
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, COFACTOR, ACTIVE SITE, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP HIS-133.
RX PubMed=23552949; DOI=10.1038/nature12038;
RA Jiang H., Khan S., Wang Y., Charron G., He B., Sebastian C., Du J., Kim R.,
RA Ge E., Mostoslavsky R., Hang H.C., Hao Q., Lin H.;
RT "SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty
RT acyl lysine.";
RL Nature 496:110-113(2013).
RN [49] {ECO:0007744|PDB:5MF6, ECO:0007744|PDB:5MFP, ECO:0007744|PDB:5MFZ, ECO:0007744|PDB:5MGN}
RP X-RAY CRYSTALLOGRAPHY (1.87 ANGSTROMS) OF 13-308 IN COMPLEX WITH UBCS039
RP ACTIVATOR AND ZINC, AND ACTIVITY REGULATION.
RX PubMed=27990725; DOI=10.1002/anie.201610082;
RA You W., Rotili D., Li T.M., Kambach C., Meleshin M., Schutkowski M.,
RA Chua K.F., Mai A., Steegborn C.;
RT "Structural basis of sirtuin 6 activation by synthetic small molecules.";
RL Angew. Chem. Int. Ed. 56:1007-1011(2017).
RN [50] {ECO:0007744|PDB:6HOY}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 13-308 IN COMPLEX WITH
RP HYDROXAMATE TRICHOSTATIN A, AND ACTIVITY REGULATION.
RX PubMed=30395713; DOI=10.1021/acs.jmedchem.8b01455;
RA You W., Steegborn C.;
RT "Structural basis of sirtuin 6 inhibition by the hydroxamate trichostatin
RT A: implications for protein deacylase drug development.";
RL J. Med. Chem. 61:10922-10928(2018).
RN [51] {ECO:0007744|PDB:5X16, ECO:0007744|PDB:5Y2F}
RP X-RAY CRYSTALLOGRAPHY (2.53 ANGSTROMS) OF 3-318 IN COMPLEX WITH COMPOUND
RP MDL-801, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS
RP OF PHE-82 AND PHE-86.
RX PubMed=30374165; DOI=10.1038/s41589-018-0150-0;
RA Huang Z., Zhao J., Deng W., Chen Y., Shang J., Song K., Zhang L., Wang C.,
RA Lu S., Yang X., He B., Min J., Hu H., Tan M., Xu J., Zhang Q., Zhong J.,
RA Sun X., Mao Z., Lin H., Xiao M., Chin Y.E., Jiang H., Xu Y., Chen G.,
RA Zhang J.;
RT "Identification of a cellularly active SIRT6 allosteric activator.";
RL Nat. Chem. Biol. 14:1118-1126(2018).
RN [52] {ECO:0007744|PDB:6QCD, ECO:0007744|PDB:6QCE, ECO:0007744|PDB:6QCH, ECO:0007744|PDB:6QCJ}
RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS) OF 13-308 IN COMPLEX WITH
RP QUERCETIN-LIKE COMPOUNDS, AND ACTIVITY REGULATION.
RX PubMed=31844103; DOI=10.1038/s41598-019-55654-1;
RA You W., Zheng W., Weiss S., Chua K.F., Steegborn C.;
RT "Structural basis for the activation and inhibition of Sirtuin 6 by
RT quercetin and its derivatives.";
RL Sci. Rep. 9:19176-19176(2019).
RN [53] {ECO:0007744|PDB:6ZU4}
RP X-RAY CRYSTALLOGRAPHY (2.46 ANGSTROMS) OF 13-308 IN COMPLEX WITH
RP FLUVASTATIN, AND ACTIVITY REGULATION.
RX PubMed=33214841; DOI=10.1021/acsmedchemlett.0c00407;
RA You W., Steegborn C.;
RT "Structural basis for activation of human sirtuin 6 by fluvastatin.";
RL ACS Med. Chem. Lett. 11:2285-2289(2020).
RN [54] {ECO:0007744|PDB:6XUY, ECO:0007744|PDB:6XV1, ECO:0007744|PDB:6XV6, ECO:0007744|PDB:6XVG}
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 3-318 IN COMPLEX WITH COMPOUND
RP MDL-801, AND ACTIVITY REGULATION.
RX PubMed=33649599; DOI=10.1038/s41589-021-00749-y;
RA You W., Steegborn C.;
RT "Binding site for activator MDL-801 on SIRT6.";
RL Nat. Chem. Biol. 17:519-521(2021).
RN [55] {ECO:0007744|PDB:7CL0, ECO:0007744|PDB:7CL1}
RP X-RAY CRYSTALLOGRAPHY (2.53 ANGSTROMS) IN COMPLEX WITH COMPOUND MDL-801,
RP AND ACTIVITY REGULATION.
RX PubMed=33649600; DOI=10.1038/s41589-021-00750-5;
RA Huang Z., Zhao J., Deng W., Chen Y., Shang J., Song K., Zhang L., Wang C.,
RA Lu S., Yang X., He B., Min J., Hu H., Tan M., Xu J., Zhang Q., Zhong J.,
RA Sun X., Mao Z., Lin H., Xiao M., Chin Y.E., Jiang H., Shen H., Xu Y.,
RA Chen G., Zhang J.;
RT "Reply to: Binding site for MDL-801 on SIRT6.";
RL Nat. Chem. Biol. 17:522-523(2021).
RN [56]
RP VARIANTS ASN-25; VAL-36; ASN-46; TYR-63; SER-89; ASN-116; 260-GLU--SER-355
RP DEL; PRO-263 AND LEU-274, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR
RP LOCATION, AND CHARACTERIZATION OF VARIANTS ASN-25; VAL-36; ASN-46; TYR-63;
RP SER-89; ASN-116; 260-GLU--SER-355 DEL; PRO-263 AND LEU-274.
RX PubMed=26456828; DOI=10.1016/j.celrep.2015.09.022;
RA Kugel S., Feldman J.L., Klein M.A., Silberman D.M., Sebastian C.,
RA Mermel C., Dobersch S., Clark A.R., Getz G., Denu J.M., Mostoslavsky R.;
RT "Identification of and molecular basis for SIRT6 loss-of-function point
RT mutations in cancer.";
RL Cell Rep. 13:479-488(2015).
RN [57]
RP VARIANT HIS-63, CHARACTERIZATION OF VARIANT HIS-63, FUNCTION, SUBCELLULAR
RP LOCATION, AND CATALYTIC ACTIVITY.
RX PubMed=29555651; DOI=10.1101/gad.307330.117;
RA Ferrer C.M., Alders M., Postma A.V., Park S., Klein M.A., Cetinbas M.,
RA Pajkrt E., Glas A., van Koningsbruggen S., Christoffels V.M.,
RA Mannens M.M.A.M., Knegt L., Etchegaray J.P., Sadreyev R.I., Denu J.M.,
RA Mostoslavsky G., van Maarle M.C., Mostoslavsky R.;
RT "An inactivating mutation in the histone deacetylase SIRT6 causes human
RT perinatal lethality.";
RL Genes Dev. 32:373-388(2018).
CC -!- FUNCTION: NAD-dependent protein deacetylase, deacylase and mono-ADP-
CC ribosyltransferase that plays an essential role in DNA damage repair,
CC telomere maintenance, metabolic homeostasis, inflammation,
CC tumorigenesis and aging (PubMed:18337721, PubMed:19135889,
CC PubMed:19625767, PubMed:21680843, PubMed:23217706, PubMed:23653361,
CC PubMed:24052263, PubMed:27322069, PubMed:27180906, PubMed:21362626,
CC PubMed:23552949, PubMed:30374165, PubMed:29555651). Displays protein-
CC lysine deacetylase or defatty-acylase (demyristoylase and
CC depalmitoylase) activity, depending on the context (PubMed:24052263,
CC PubMed:27322069, PubMed:23552949). Acts as a key histone deacetylase by
CC catalyzing deacetylation of histone H3 at 'Lys-9', 'Lys-18' and 'Lys-
CC 56' (H3K9ac, H3K18ac and H3K56ac, respectively), suppressing target
CC gene expression of several transcription factors, including NF-kappa-B
CC (PubMed:19625767, PubMed:24012758, PubMed:23892288, PubMed:23911928,
CC PubMed:27043296, PubMed:26898756, PubMed:27180906, PubMed:33067423,
CC PubMed:21362626, PubMed:30374165, PubMed:26456828). Acts as an
CC inhibitor of transcription elongation by mediating deacetylation of
CC H3K9ac and H3K56ac, preventing release of NELFE from chromatin and
CC causing transcriptional pausing (By similarity). Involved in DNA repair
CC by promoting double-strand break (DSB) repair: acts as a DSB sensor by
CC recognizing and binding DSB sites, leading to (1) recruitment of DNA
CC repair proteins, such as SMARCA5/SNF2H, and (2) deacetylation of
CC histone H3K9ac and H3K56ac (PubMed:23911928, PubMed:31995034,
CC PubMed:32538779). SIRT6 participation to DSB repair is probably
CC involved in extension of life span (By similarity). Also promotes DNA
CC repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53
CC (PubMed:32789493, PubMed:29474172). Specifically deacetylates H3K18ac
CC at pericentric heterochromatin, thereby maintaining pericentric
CC heterochromatin silencing at centromeres and protecting against genomic
CC instability and cellular senescence (PubMed:27043296). Involved in
CC telomere maintenance by catalyzing deacetylation of histone H3 in
CC telomeric chromatin, regulating telomere position effect and telomere
CC movement in response to DNA damage (PubMed:18337721, PubMed:19625767,
CC PubMed:21847107). Required for embryonic stem cell differentiation by
CC mediating histone deacetylation of H3K9ac (PubMed:25915124,
CC PubMed:29555651). Plays a major role in metabolism by regulating
CC processes such as glycolysis, gluconeogenesis, insulin secretion and
CC lipid metabolism (PubMed:24012758, PubMed:26787900). Inhibits
CC glycolysis via histone deacetylase activity and by acting as a
CC corepressor of the transcription factor HIF1A, thereby controlling the
CC expression of multiple glycolytic genes (By similarity). Has tumor
CC suppressor activity by repressing glycolysis, thereby inhibiting the
CC Warburg effect (PubMed:23217706). Also regulates glycolysis and
CC tumorigenesis by mediating deacetylation and nuclear export of non-
CC histone proteins, such as isoform M2 of PKM (PKM2) (PubMed:26787900).
CC Acts as a negative regulator of gluconeogenesis by mediating
CC deacetylation of non-histone proteins, such as FOXO1 and KAT2A/GCN5
CC (PubMed:23142079, PubMed:25009184). Promotes beta-oxidation of fatty
CC acids during fasting by catalyzing deacetylation of NCOA2, inducing
CC coactivation of PPARA (By similarity). Acts as a regulator of lipid
CC catabolism in brown adipocytes, both by catalyzing deacetylation of
CC histones and non-histone proteins, such as FOXO1 (By similarity). Also
CC acts as a regulator of circadian rhythms, both by regulating expression
CC of clock-controlled genes involved in lipid and carbohydrate
CC metabolism, and by catalyzing deacetylation of PER2 (By similarity).
CC The defatty-acylase activity is specifically involved in regulation of
CC protein secretion (PubMed:24052263, PubMed:23552949, PubMed:27322069,
CC PubMed:28406396). Has high activity toward long-chain fatty acyl groups
CC and mediates protein-lysine demyristoylation and depalmitoylation of
CC target proteins, such as RRAS2 and TNF, thereby regulating their
CC secretion (PubMed:23552949, PubMed:28406396). Also acts as a mono-ADP-
CC ribosyltransferase by mediating mono-ADP-ribosylation of PARP1,
CC TRIM28/KAP1 or SMARCC2/BAF170 (PubMed:21680843, PubMed:22753495,
CC PubMed:27568560, PubMed:27322069). Mono-ADP-ribosyltransferase activity
CC is involved in DNA repair, cellular senescence, repression of LINE-1
CC retrotransposon elements and regulation of transcription
CC (PubMed:21680843, PubMed:22753495, PubMed:27568560).
CC {ECO:0000250|UniProtKB:P59941, ECO:0000269|PubMed:18337721,
CC ECO:0000269|PubMed:19135889, ECO:0000269|PubMed:19625767,
CC ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:21680843,
CC ECO:0000269|PubMed:21847107, ECO:0000269|PubMed:22753495,
CC ECO:0000269|PubMed:23142079, ECO:0000269|PubMed:23217706,
CC ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:23653361,
CC ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:23911928,
CC ECO:0000269|PubMed:24012758, ECO:0000269|PubMed:24052263,
CC ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:25915124,
CC ECO:0000269|PubMed:26456828, ECO:0000269|PubMed:26787900,
CC ECO:0000269|PubMed:26898756, ECO:0000269|PubMed:27043296,
CC ECO:0000269|PubMed:27180906, ECO:0000269|PubMed:27322069,
CC ECO:0000269|PubMed:27568560, ECO:0000269|PubMed:28406396,
CC ECO:0000269|PubMed:29474172, ECO:0000269|PubMed:29555651,
CC ECO:0000269|PubMed:30374165, ECO:0000269|PubMed:31995034,
CC ECO:0000269|PubMed:32538779, ECO:0000269|PubMed:32789493,
CC ECO:0000269|PubMed:33067423}.
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 ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:23142079,
CC ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:24052263,
CC ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:26456828,
CC ECO:0000269|PubMed:26787900, ECO:0000269|PubMed:27043296,
CC ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:27912097,
CC ECO:0000269|PubMed:29474172, ECO:0000269|PubMed:29555651,
CC ECO:0000269|PubMed:30374165, ECO:0000269|PubMed:32789493,
CC ECO:0000269|PubMed:33067423, ECO:0000269|PubMed:33122195};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43637;
CC Evidence={ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:23142079,
CC ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:24052263,
CC ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:26456828,
CC ECO:0000269|PubMed:26787900, ECO:0000269|PubMed:27043296,
CC ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:27912097,
CC ECO:0000269|PubMed:29474172, ECO:0000269|PubMed:29555651,
CC ECO:0000269|PubMed:30374165, ECO:0000269|PubMed:32789493,
CC ECO:0000269|PubMed:33067423, ECO:0000269|PubMed:33122195};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-tetradecanoyl-L-lysyl-[protein] + NAD(+) = 2''-O-
CC tetradecanoyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:70567, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:15437,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:141129, ChEBI:CHEBI:189674;
CC Evidence={ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:24052263,
CC ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:29555651};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70568;
CC Evidence={ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:24052263,
CC ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:29555651};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-hexadecanoyl-L-lysyl-[protein] + NAD(+) = 2''-O-
CC hexadecanoyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:70563, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:14175,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:138936, ChEBI:CHEBI:189673;
CC Evidence={ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:24052263,
CC ECO:0000269|PubMed:27322069};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70564;
CC Evidence={ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:24052263,
CC ECO:0000269|PubMed:27322069};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-lysyl-[protein] + NAD(+) = H(+) + N(6)-(ADP-D-ribosyl)-L-
CC lysyl-[protein] + nicotinamide; Xref=Rhea:RHEA:58220, Rhea:RHEA-
CC COMP:9752, Rhea:RHEA-COMP:15088, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:29969, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:142515; Evidence={ECO:0000269|PubMed:21680843,
CC ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:27568560};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58221;
CC Evidence={ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:27322069,
CC ECO:0000269|PubMed:27568560};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-arginyl-[protein] + NAD(+) = H(+) + N(omega)-(ADP-D-
CC ribosyl)-L-arginyl-[protein] + nicotinamide; Xref=Rhea:RHEA:19149,
CC Rhea:RHEA-COMP:10532, Rhea:RHEA-COMP:15087, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:29965, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:142554; Evidence={ECO:0000250|UniProtKB:P59941};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19150;
CC Evidence={ECO:0000250|UniProtKB:P59941};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:23552949,
CC ECO:0000269|PubMed:27990725};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:21362626,
CC ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:27990725};
CC -!- ACTIVITY REGULATION: Compared to the defatty-acylase activity, the
CC protein deacetylase activity is weak in vitro, and requires activation
CC (PubMed:24052263, PubMed:23892288, PubMed:21362626, PubMed:23552949).
CC The histone deacetylase activity is strongly activated upon binding to
CC nucleosomes and chromatin in vivo (PubMed:23892288, PubMed:27043296,
CC PubMed:33067423). Two molecules of SIRT6 associate with the acidic
CC patch of one nucleosome, while the C-terminal disordered region of
CC SIRT6 associates with nucleosomal DNA, leading to efficient histone
CC deacetylation (PubMed:33067423). The protein-lysine deacetylase
CC activity is also activated by long-chain free fatty-acids
CC (PubMed:24052263). The histone deacetylase activity is specifically
CC repressed by long non-coding RNA lncPRESS1, which binds to SIRT6 and
CC prevents chromatin-binding, thereby promoting stem cell pluripotency
CC (PubMed:27912097). Due to its essential role as tumor suppressor and
CC involvement in DNA repair and life span, extensive research is made for
CC the identification of small compound regulators of SIRT6
CC (PubMed:27990725, PubMed:30395713, PubMed:30374165, PubMed:31844103,
CC PubMed:33214841, PubMed:33649599, PubMed:33649600). Nitro-fatty acids
CC (nitro-oleic acid and nitro-conjugated linoleic acid) strongly
CC stimulate the protein-lysine deacetylase activity by forming a covalent
CC Michael adduct formation with Cys-18 (PubMed:33122195). Activated by
CC UBCS039 (4-(pyridin-3-yl)-4,5- dihydropyrrolo[1,2-a]quinoxaline)
CC (PubMed:27990725). Inhibited by non-selective hydroxamate trichostatin
CC A inhibitor (PubMed:30395713). Deacetylase activity is activated by
CC fluvastatin and quercetin-based compounds (PubMed:31844103,
CC PubMed:33214841). The protein-lysine deacetylase activity, but not the
CC defatty-acylase activity, is specifically activated by MDL-800 and MDL-
CC 801 activators in vivo, enhancing the histone deacetylase and tumor
CC suppressor activities (PubMed:30374165, PubMed:33649599,
CC PubMed:33649600). MDL-800 and MDL-801 selectively activate SIRT6 and
CC not other members of the sirtuin family (PubMed:30374165). The binding-
CC mode of MDL-801 is however subject to discussion (PubMed:30374165,
CC PubMed:33649599, PubMed:33649600). {ECO:0000269|PubMed:21362626,
CC ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:23892288,
CC ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:27043296,
CC ECO:0000269|PubMed:27912097, ECO:0000269|PubMed:27990725,
CC ECO:0000269|PubMed:30374165, ECO:0000269|PubMed:30395713,
CC ECO:0000269|PubMed:31844103, ECO:0000269|PubMed:33067423,
CC ECO:0000269|PubMed:33122195, ECO:0000269|PubMed:33214841,
CC ECO:0000269|PubMed:33649599, ECO:0000269|PubMed:33649600}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=3.4 uM for N6-tetradecanoyl-L-lysyl-peptide (myristoylated
CC peptide) {ECO:0000269|PubMed:23552949};
CC KM=0.9 uM for N6-hexadecanoyl-L-lysyl-peptide (palmitoylated peptide)
CC {ECO:0000269|PubMed:23552949};
CC KM=2.4 uM for N6-tetradecanoyl-L-lysyl-TNF (TNF myristoylated on
CC 'Lys-19') {ECO:0000269|PubMed:23552949};
CC KM=4.5 uM for N6-tetradecanoyl-L-lysyl-TNF (TNF myristoylated on
CC 'Lys-20') {ECO:0000269|PubMed:23552949};
CC Note=kcat is 0.0049 sec(-1) for N6-tetradecanoyl-L-lysyl-peptide
CC (myristoylated peptide) (PubMed:23552949). kcat is 0.0027 sec(-1) for
CC N6-hexadecanoyl-L-lysyl-peptide (palmitoylated peptide)
CC (PubMed:23552949). kcat is 0.0020 sec(-1) for N6-tetradecanoyl-L-
CC lysyl-TNF (TNF myristoylated on 'Lys-19') (PubMed:23552949). kcat is
CC 0.0050 sec(-1) for N6-tetradecanoyl-L-lysyl-TNF (TNF myristoylated on
CC 'Lys-20') (PubMed:23552949). {ECO:0000269|PubMed:23552949};
CC -!- SUBUNIT: Homodimer; binds to nucleosomes and DNA ends as a homodimer
CC (PubMed:31995034, PubMed:32538779). Interacts with RELA; interferes
CC with RELA binding to target DNA (PubMed:19135889). Interacts with
CC SMARCA5; promoting recruitment of SMARCA5/SNF2H to double-strand breaks
CC (DSBs) sites (PubMed:23911928). Interacts with the mTORC2 complex;
CC preventing the ability of SIRT6 to deacetylate FOXO1. Interacts with
CC the CLOCK-BMAL1 complex; recruited by the CLOCK-BMAL1 complex to
CC regulate expression of clock-controlled genes. Interacts with CSNK2A2;
CC preventing CSNK2A2 localization to the nucleus (By similarity).
CC {ECO:0000250|UniProtKB:P59941, ECO:0000269|PubMed:19135889,
CC ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:31995034,
CC ECO:0000269|PubMed:32538779}.
CC -!- INTERACTION:
CC Q8N6T7; P01106: MYC; NbExp=3; IntAct=EBI-712415, EBI-447544;
CC Q8N6T7; Q04206: RELA; NbExp=4; IntAct=EBI-712415, EBI-73886;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16079181,
CC ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:19135889,
CC ECO:0000269|PubMed:26456828, ECO:0000269|PubMed:26898756,
CC ECO:0000269|PubMed:29555651}. Chromosome {ECO:0000269|PubMed:21680843,
CC ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:26456828,
CC ECO:0000269|PubMed:27043296, ECO:0000269|PubMed:27568560,
CC ECO:0000269|PubMed:27912097, ECO:0000269|PubMed:31995034,
CC ECO:0000269|PubMed:32538779, ECO:0000269|PubMed:32789493}. Chromosome,
CC telomere {ECO:0000269|PubMed:18337721}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:23552949}. Note=Predominantly nuclear
CC (PubMed:18337721). Associated with pericentric heterochromatin and
CC telomeric heterochromatin regions (PubMed:18337721, PubMed:27043296).
CC Localizes to DNA damage sites: directly recognizes and binds double-
CC strand breaks (DSBs) sites via a tunnel-like structure that has high
CC affinity for DSBs (PubMed:21680843, PubMed:23911928, PubMed:27568560,
CC PubMed:31995034, PubMed:32538779). A fraction localizes to the
CC endoplasmic reticulum (PubMed:23552949). {ECO:0000269|PubMed:18337721,
CC ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:23552949,
CC ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:27043296,
CC ECO:0000269|PubMed:27568560, ECO:0000269|PubMed:31995034,
CC ECO:0000269|PubMed:32538779}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8N6T7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8N6T7-2; Sequence=VSP_008733;
CC -!- INDUCTION: Down-regulated in a number of cancers, such as pancreatic
CC cancer or colon carcinomas (PubMed:23217706). Post-transcriptionally
CC regulated by miR-766 (PubMed:23653361). Expression is post-
CC transcriptionally repressed by miR-122 (PubMed:26748705).
CC {ECO:0000269|PubMed:23217706, ECO:0000269|PubMed:23653361,
CC ECO:0000269|PubMed:26748705}.
CC -!- DOMAIN: The C-terminal disordered region mediates non-specific DNA-
CC binding. {ECO:0000269|PubMed:33067423}.
CC -!- PTM: Acetylated at Lys-33 (PubMed:32538779). Deacetylation at Lys-33 by
CC SIRT1 promotes homomultimerization and binding to double-strand breaks
CC (DSBs) sites (PubMed:32538779). {ECO:0000269|PubMed:32538779}.
CC -!- PTM: Phosphorylation at Ser-10 by MAPK8/JNK1 in response to oxidative
CC stress stimulates the mono-ADP-ribosyltransferase activity on PARP1,
CC leading to PARP1 recruitment to double-strand breaks (DSBs).
CC {ECO:0000269|PubMed:27568560}.
CC -!- PTM: Monoubiquitinated at Lys-170 by STUB1/CHIP, preventing its
CC degradation by the proteasome. {ECO:0000269|PubMed:24043303}.
CC -!- PTM: Sumoylated, leading to specifically decrease ability to
CC deacetylate histone H3 at 'Lys-56' (H3K56ac).
CC {ECO:0000269|PubMed:26898756}.
CC -!- POLYMORPHISM: Variability among SIRT6 alleles may account for
CC variations in life span (PubMed:25541994). A minor allele (rs107251) is
CC associated with a decreased life span of 5.5 and 5.9 years when
CC homozygous (TT); when compared to the major allele homozygous (CC) and
CC heterozygous (CT) genotypes, respectively (PubMed:25541994).
CC {ECO:0000269|PubMed:25541994}.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class IV subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: Upon DNA damage, was reported to promote DNA end resection via
CC deacetylation of RBBP8. However, this study was later retracted.
CC {ECO:0000305|PubMed:20829486, ECO:0000305|PubMed:30975768}.
CC -!- CAUTION: The binding-mode of MDL-801 selective activator is subject to
CC discussion (PubMed:30374165, PubMed:33649599, PubMed:33649600).
CC According to a group, MDL-801 binds around the acyl channel exit and
CC acts as an allosteric activator (PubMed:30374165, PubMed:33649600).
CC According to another group, the binding mode of MDL-801 remains
CC undefined (PubMed:33649599). {ECO:0000269|PubMed:30374165,
CC ECO:0000269|PubMed:33649599, ECO:0000269|PubMed:33649600}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC34468.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC Sequence=AAD15478.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC Sequence=AAH04218.1; Type=Erroneous translation; Note=Wrong choice of CCDS.; Evidence={ECO:0000305};
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DR EMBL; AF233396; AAF43432.1; -; mRNA.
DR EMBL; AK074810; BAC11222.1; -; mRNA.
DR EMBL; AK315048; BAG37527.1; -; mRNA.
DR EMBL; CR457200; CAG33481.1; -; mRNA.
DR EMBL; AC005620; AAC34468.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC006930; AAD15478.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471139; EAW69252.1; -; Genomic_DNA.
DR EMBL; BC004218; AAH04218.1; ALT_SEQ; mRNA.
DR EMBL; BC005026; AAH05026.1; -; mRNA.
DR EMBL; BC028220; AAH28220.1; -; mRNA.
DR CCDS; CCDS12122.1; -. [Q8N6T7-1]
DR CCDS; CCDS54199.1; -. [Q8N6T7-2]
DR RefSeq; NP_001180214.1; NM_001193285.2. [Q8N6T7-2]
DR RefSeq; NP_001307987.1; NM_001321058.1.
DR RefSeq; NP_001307988.1; NM_001321059.1.
DR RefSeq; NP_001307989.1; NM_001321060.1.
DR RefSeq; NP_001307990.1; NM_001321061.1.
DR RefSeq; NP_001307991.1; NM_001321062.1.
DR RefSeq; NP_001307992.1; NM_001321063.1.
DR RefSeq; NP_001307993.1; NM_001321064.1.
DR RefSeq; NP_057623.2; NM_016539.3. [Q8N6T7-1]
DR PDB; 3K35; X-ray; 2.00 A; A/B/C/D/E/F=3-318.
DR PDB; 3PKI; X-ray; 2.04 A; A/B/C/D/E/F=2-355.
DR PDB; 3PKJ; X-ray; 2.12 A; A/B/C/D/E/F=2-355.
DR PDB; 3ZG6; X-ray; 2.20 A; A=1-296.
DR PDB; 5MF6; X-ray; 1.87 A; A/B=13-308.
DR PDB; 5MFP; X-ray; 1.98 A; A/B=13-308.
DR PDB; 5MFZ; X-ray; 2.10 A; A/B=13-308.
DR PDB; 5MGN; X-ray; 2.07 A; A/B=13-308.
DR PDB; 5X16; X-ray; 1.97 A; A=3-318.
DR PDB; 5Y2F; X-ray; 2.53 A; A=3-318.
DR PDB; 6HOY; X-ray; 1.70 A; A/B=13-308.
DR PDB; 6QCD; X-ray; 1.84 A; A/B=13-308.
DR PDB; 6QCE; X-ray; 1.90 A; A/B=13-308.
DR PDB; 6QCH; X-ray; 2.10 A; A/B=13-308.
DR PDB; 6QCJ; X-ray; 2.01 A; A/B=13-308.
DR PDB; 6XUY; X-ray; 2.13 A; A/B=13-308.
DR PDB; 6XV1; X-ray; 1.95 A; A/B=13-308.
DR PDB; 6XV6; X-ray; 1.75 A; A/B/C/D/E/F=3-318.
DR PDB; 6XVG; X-ray; 2.10 A; A/B/C/D/E/F=3-318.
DR PDB; 6ZU4; X-ray; 2.46 A; A/B=13-308.
DR PDB; 7CL0; X-ray; 2.53 A; A=1-355.
DR PDB; 7CL1; X-ray; 3.20 A; A=1-355.
DR PDBsum; 3K35; -.
DR PDBsum; 3PKI; -.
DR PDBsum; 3PKJ; -.
DR PDBsum; 3ZG6; -.
DR PDBsum; 5MF6; -.
DR PDBsum; 5MFP; -.
DR PDBsum; 5MFZ; -.
DR PDBsum; 5MGN; -.
DR PDBsum; 5X16; -.
DR PDBsum; 5Y2F; -.
DR PDBsum; 6HOY; -.
DR PDBsum; 6QCD; -.
DR PDBsum; 6QCE; -.
DR PDBsum; 6QCH; -.
DR PDBsum; 6QCJ; -.
DR PDBsum; 6XUY; -.
DR PDBsum; 6XV1; -.
DR PDBsum; 6XV6; -.
DR PDBsum; 6XVG; -.
DR PDBsum; 6ZU4; -.
DR PDBsum; 7CL0; -.
DR PDBsum; 7CL1; -.
DR AlphaFoldDB; Q8N6T7; -.
DR SMR; Q8N6T7; -.
DR BioGRID; 119603; 629.
DR DIP; DIP-47346N; -.
DR IntAct; Q8N6T7; 71.
DR MINT; Q8N6T7; -.
DR STRING; 9606.ENSP00000337332; -.
DR BindingDB; Q8N6T7; -.
DR ChEMBL; CHEMBL2163182; -.
DR GuidetoPHARMACOLOGY; 2712; -.
DR iPTMnet; Q8N6T7; -.
DR PhosphoSitePlus; Q8N6T7; -.
DR BioMuta; SIRT6; -.
DR DMDM; 38258612; -.
DR EPD; Q8N6T7; -.
DR jPOST; Q8N6T7; -.
DR MassIVE; Q8N6T7; -.
DR MaxQB; Q8N6T7; -.
DR PaxDb; Q8N6T7; -.
DR PeptideAtlas; Q8N6T7; -.
DR PRIDE; Q8N6T7; -.
DR ProteomicsDB; 72232; -. [Q8N6T7-1]
DR ProteomicsDB; 72233; -. [Q8N6T7-2]
DR Antibodypedia; 11389; 711 antibodies from 42 providers.
DR DNASU; 51548; -.
DR Ensembl; ENST00000305232.10; ENSP00000305310.5; ENSG00000077463.15. [Q8N6T7-2]
DR Ensembl; ENST00000337491.7; ENSP00000337332.1; ENSG00000077463.15. [Q8N6T7-1]
DR GeneID; 51548; -.
DR KEGG; hsa:51548; -.
DR MANE-Select; ENST00000337491.7; ENSP00000337332.1; NM_016539.4; NP_057623.2.
DR UCSC; uc002lzo.4; human. [Q8N6T7-1]
DR CTD; 51548; -.
DR DisGeNET; 51548; -.
DR GeneCards; SIRT6; -.
DR HGNC; HGNC:14934; SIRT6.
DR HPA; ENSG00000077463; Low tissue specificity.
DR MalaCards; SIRT6; -.
DR MIM; 606211; gene.
DR neXtProt; NX_Q8N6T7; -.
DR OpenTargets; ENSG00000077463; -.
DR Orphanet; 580933; Lethal brain and heart developmental defects.
DR PharmGKB; PA37939; -.
DR VEuPathDB; HostDB:ENSG00000077463; -.
DR eggNOG; KOG1905; Eukaryota.
DR GeneTree; ENSGT00940000160088; -.
DR HOGENOM; CLU_023643_6_0_1; -.
DR InParanoid; Q8N6T7; -.
DR OMA; EQCKKCR; -.
DR OrthoDB; 1503290at2759; -.
DR PhylomeDB; Q8N6T7; -.
DR TreeFam; TF106184; -.
DR BRENDA; 2.3.1.B41; 2681.
DR PathwayCommons; Q8N6T7; -.
DR Reactome; R-HSA-1912408; Pre-NOTCH Transcription and Translation.
DR Reactome; R-HSA-5693607; Processing of DNA double-strand break ends.
DR SignaLink; Q8N6T7; -.
DR SIGNOR; Q8N6T7; -.
DR BioGRID-ORCS; 51548; 32 hits in 1103 CRISPR screens.
DR ChiTaRS; SIRT6; human.
DR EvolutionaryTrace; Q8N6T7; -.
DR GeneWiki; SIRT6; -.
DR GenomeRNAi; 51548; -.
DR Pharos; Q8N6T7; Tchem.
DR PRO; PR:Q8N6T7; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q8N6T7; protein.
DR Bgee; ENSG00000077463; Expressed in mucosa of transverse colon and 133 other tissues.
DR ExpressionAtlas; Q8N6T7; baseline and differential.
DR Genevisible; Q8N6T7; HS.
DR GO; GO:0000785; C:chromatin; IDA:UniProtKB.
DR GO; GO:0099115; C:chromosome, subtelomeric region; IDA:GO_Central.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005721; C:pericentric heterochromatin; IDA:UniProtKB.
DR GO; GO:0090734; C:site of DNA damage; IDA:UniProtKB.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0031490; F:chromatin DNA binding; IDA:UniProtKB.
DR GO; GO:0003684; F:damaged DNA binding; IDA:UniProtKB.
DR GO; GO:0019213; F:deacetylase activity; IBA:GO_Central.
DR GO; GO:0140612; F:DNA damage sensor activity; IDA:UniProtKB.
DR GO; GO:0004407; F:histone deacetylase activity; IBA:GO_Central.
DR GO; GO:0106222; F:lncRNA binding; IDA:UniProtKB.
DR GO; GO:0003950; F:NAD+ ADP-ribosyltransferase activity; TAS:BHF-UCL.
DR GO; GO:0070403; F:NAD+ binding; ISS:UniProtKB.
DR GO; GO:1990404; F:NAD+-protein ADP-ribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0106274; F:NAD+-protein-arginine ADP-ribosyltransferase activity; ISS:UniProtKB.
DR GO; GO:0017136; F:NAD-dependent histone deacetylase activity; ISS:UniProtKB.
DR GO; GO:0097372; F:NAD-dependent histone deacetylase activity (H3-K18 specific); IDA:UniProtKB.
DR GO; GO:0140765; F:NAD-dependent histone deacetylase activity (H3-K56 specific); IDA:UniProtKB.
DR GO; GO:0046969; F:NAD-dependent histone deacetylase activity (H3-K9 specific); IDA:UniProtKB.
DR GO; GO:0034979; F:NAD-dependent protein deacetylase activity; IDA:UniProtKB.
DR GO; GO:0140773; F:NAD-dependent protein demyristoylase activity; IDA:UniProtKB.
DR GO; GO:0140774; F:NAD-dependent protein depalmitoylase activity; IDA:UniProtKB.
DR GO; GO:0031491; F:nucleosome binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:1904841; F:TORC2 complex binding; ISS:UniProtKB.
DR GO; GO:0003714; F:transcription corepressor activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0006284; P:base-excision repair; IEA:Ensembl.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl.
DR GO; GO:0070932; P:histone H3 deacetylation; IBA:GO_Central.
DR GO; GO:0042181; P:ketone biosynthetic process; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:2000773; P:negative regulation of cellular senescence; IDA:UniProtKB.
DR GO; GO:0045814; P:negative regulation of gene expression, epigenetic; IMP:BHF-UCL.
DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IDA:UniProtKB.
DR GO; GO:0046325; P:negative regulation of glucose import; IEA:Ensembl.
DR GO; GO:0045820; P:negative regulation of glycolytic process; IDA:UniProtKB.
DR GO; GO:0042308; P:negative regulation of protein import into nucleus; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0010529; P:negative regulation of transposition; ISS:UniProtKB.
DR GO; GO:0031508; P:pericentric heterochromatin assembly; IDA:UniProtKB.
DR GO; GO:1905555; P:positive regulation of blood vessel branching; IMP:BHF-UCL.
DR GO; GO:1902732; P:positive regulation of chondrocyte proliferation; IMP:BHF-UCL.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:UniProtKB.
DR GO; GO:2000781; P:positive regulation of double-strand break repair; IDA:UniProtKB.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IEA:Ensembl.
DR GO; GO:0032024; P:positive regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IDA:UniProtKB.
DR GO; GO:0120187; P:positive regulation of protein localization to chromatin; ISS:UniProtKB.
DR GO; GO:2000738; P:positive regulation of stem cell differentiation; ISS:UniProtKB.
DR GO; GO:2000648; P:positive regulation of stem cell proliferation; IEA:Ensembl.
DR GO; GO:0032206; P:positive regulation of telomere maintenance; IMP:BHF-UCL.
DR GO; GO:1901485; P:positive regulation of transcription factor catabolic process; IMP:CACAO.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0006471; P:protein ADP-ribosylation; ISS:UniProtKB.
DR GO; GO:0006476; P:protein deacetylation; IMP:CACAO.
DR GO; GO:0051697; P:protein delipidation; IDA:UniProtKB.
DR GO; GO:0031648; P:protein destabilization; IMP:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0010569; P:regulation of double-strand break repair via homologous recombination; IDA:UniProtKB.
DR GO; GO:0050994; P:regulation of lipid catabolic process; ISS:UniProtKB.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISS:UniProtKB.
DR GO; GO:0009411; P:response to UV; IDA:UniProtKB.
DR GO; GO:0031509; P:subtelomeric heterochromatin assembly; IMP:BHF-UCL.
DR IDEAL; IID00486; -.
DR InterPro; IPR029035; DHS-like_NAD/FAD-binding_dom.
DR InterPro; IPR003000; Sirtuin.
DR InterPro; IPR026590; Ssirtuin_cat_dom.
DR Pfam; PF02146; SIR2; 2.
DR SUPFAM; SSF52467; SSF52467; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Acyltransferase; Alternative splicing;
KW Chromatin regulator; Chromosome; Developmental protein; Disease variant;
KW DNA damage; DNA repair; DNA-binding; Endoplasmic reticulum;
KW Glycosyltransferase; Isopeptide bond; Metal-binding; NAD;
KW Nucleotidyltransferase; Nucleus; Phosphoprotein; Reference proteome;
KW RNA-binding; Telomere; Transferase; Tumor suppressor; Ubl conjugation;
KW Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330"
FT CHAIN 2..355
FT /note="NAD-dependent protein deacylase sirtuin-6"
FT /id="PRO_0000110269"
FT DOMAIN 35..274
FT /note="Deacetylase sirtuin-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT REGION 284..355
FT /note="Disordered"
FT /evidence="ECO:0000269|PubMed:33067423"
FT ACT_SITE 133
FT /note="Proton acceptor"
FT /evidence="ECO:0000269|PubMed:18337721,
FT ECO:0000305|PubMed:23552949, ECO:0000305|PubMed:23892288,
FT ECO:0000305|PubMed:27322069, ECO:0000305|PubMed:28406396"
FT BINDING 53
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000305|PubMed:21362626,
FT ECO:0007744|PDB:3K35, ECO:0007744|PDB:3ZG6"
FT BINDING 57
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 64
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 65
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 71
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 113
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 133
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 141
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236,
FT ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:23552949,
FT ECO:0000269|PubMed:27990725, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3PKI, ECO:0007744|PDB:3PKJ,
FT ECO:0007744|PDB:3ZG6, ECO:0007744|PDB:5MF6,
FT ECO:0007744|PDB:5MFP, ECO:0007744|PDB:5MFZ,
FT ECO:0007744|PDB:5MGN"
FT BINDING 144
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236,
FT ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:23552949,
FT ECO:0000269|PubMed:27990725, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3PKI, ECO:0007744|PDB:3PKJ,
FT ECO:0007744|PDB:3ZG6, ECO:0007744|PDB:5MF6,
FT ECO:0007744|PDB:5MFP, ECO:0007744|PDB:5MFZ,
FT ECO:0007744|PDB:5MGN"
FT BINDING 166
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236,
FT ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:23552949,
FT ECO:0000269|PubMed:27990725, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3PKI, ECO:0007744|PDB:3PKJ,
FT ECO:0007744|PDB:3ZG6, ECO:0007744|PDB:5MF6,
FT ECO:0007744|PDB:5MFP, ECO:0007744|PDB:5MFZ,
FT ECO:0007744|PDB:5MGN"
FT BINDING 177
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236,
FT ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:23552949,
FT ECO:0000269|PubMed:27990725, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3PKI, ECO:0007744|PDB:3PKJ,
FT ECO:0007744|PDB:3ZG6, ECO:0007744|PDB:5MF6,
FT ECO:0007744|PDB:5MFP, ECO:0007744|PDB:5MFZ,
FT ECO:0007744|PDB:5MGN"
FT BINDING 214
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 216
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 240
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 242
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT BINDING 258
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:23552949,
FT ECO:0000305|PubMed:21362626, ECO:0007744|PDB:3K35,
FT ECO:0007744|PDB:3ZG6"
FT SITE 18
FT /note="Formation of an covalent adduct with nitro-fatty
FT acid activators"
FT /evidence="ECO:0000269|PubMed:33122195"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 10
FT /note="Phosphoserine; by MAPK8"
FT /evidence="ECO:0000269|PubMed:27568560,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 33
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32538779"
FT MOD_RES 294
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 303
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 330
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 170
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:24043303"
FT VAR_SEQ 179..205
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_008733"
FT VARIANT 25
FT /note="D -> N (found in non-small cell lung cancer; somatic
FT mutation; reduced localization to chromatin; reduced
FT histone deacetylase activity; does not affect the protein-
FT lysine demyristoylase activity)"
FT /evidence="ECO:0000269|PubMed:26456828"
FT /id="VAR_086083"
FT VARIANT 36
FT /note="E -> V (found in kidney cancer; somatic mutation;
FT reduced histone deacetylase activity; does not affect the
FT protein-lysine demyristoylase activity)"
FT /evidence="ECO:0000269|PubMed:26456828"
FT /id="VAR_086084"
FT VARIANT 46
FT /note="S -> N (does not affect histone deacetylase
FT activity; dbSNP:rs352493)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:26456828,
FT ECO:0000269|Ref.5"
FT /id="VAR_017154"
FT VARIANT 63
FT /note="D -> H (found in a family presenting with four cases
FT of perinatal lethality caused by severe neurodevelopmental
FT and cardiac anomalies; abolished histone deacetylase
FT activity; abolished protein demyristoylase activity;
FT decreased ability to recognize and bind double-strand
FT breaks (DSBs) sites; does not affect nuclear localization)"
FT /evidence="ECO:0000269|PubMed:29555651,
FT ECO:0000269|PubMed:31995034"
FT /id="VAR_086085"
FT VARIANT 63
FT /note="D -> Y (found in non-small cell lung cancer; somatic
FT mutation; does not affect ability to recognize and bind
FT double-strand breaks (DSBs) sites; strongly reduced histone
FT deacetylase activity; strongly reduced the protein-lysine
FT demyristoylase activity)"
FT /evidence="ECO:0000269|PubMed:26456828,
FT ECO:0000269|PubMed:31995034"
FT /id="VAR_086086"
FT VARIANT 89
FT /note="A -> S (found in non-small cell lung cancer; somatic
FT mutation; reduced histone deacetylase activity; does not
FT affect the protein-lysine demyristoylase activity)"
FT /evidence="ECO:0000269|PubMed:26456828"
FT /id="VAR_086087"
FT VARIANT 116
FT /note="D -> N (found in non-small cell lung cancer; somatic
FT mutation; reduced localization to chromatin; strongly
FT reduced histone deacetylase activity; strongly reduced the
FT protein-lysine demyristoylase activity)"
FT /evidence="ECO:0000269|PubMed:26456828"
FT /id="VAR_086088"
FT VARIANT 260..355
FT /note="Missing (found in non-small cell lung cancer;
FT somatic mutation; reduced localization to chromatin)"
FT /evidence="ECO:0000269|PubMed:26456828"
FT /id="VAR_086089"
FT VARIANT 263
FT /note="T -> P (found in cervical cancer; somatic mutation;
FT reduced histone deacetylase activity; slightly reduced the
FT protein-lysine demyristoylase activity)"
FT /evidence="ECO:0000269|PubMed:26456828"
FT /id="VAR_086090"
FT VARIANT 274
FT /note="P -> L (found in melanoma; somatic mutation; reduced
FT histone deacetylase activity; does not affect the protein-
FT lysine demyristoylase activity)"
FT /evidence="ECO:0000269|PubMed:26456828"
FT /id="VAR_086091"
FT MUTAGEN 10
FT /note="S->A: Abolihes ability to promote DNA repair and
FT recruit PARP1 to double-strand breaks (DSBs)."
FT /evidence="ECO:0000269|PubMed:27568560"
FT MUTAGEN 10
FT /note="S->E: Mimics phosphorylation; increased ability to
FT promote DNA repair and recruit PARP1 to double-strand
FT breaks (DSBs)."
FT /evidence="ECO:0000269|PubMed:27568560"
FT MUTAGEN 13
FT /note="A->W: Increased protein-lysine demyristoylase
FT activity."
FT /evidence="ECO:0000269|PubMed:31995034"
FT MUTAGEN 15
FT /note="K->R: Does not affect acetylation level."
FT /evidence="ECO:0000269|PubMed:32538779"
FT MUTAGEN 17
FT /note="K->R: Does not affect acetylation level."
FT /evidence="ECO:0000269|PubMed:32538779"
FT MUTAGEN 33
FT /note="K->Q: Mimics acetylation, leading to impaired
FT ability to recognize and bind double-strand breaks (DSBs)
FT sites."
FT /evidence="ECO:0000269|PubMed:32538779"
FT MUTAGEN 33
FT /note="K->R: Decreased acetylation level."
FT /evidence="ECO:0000269|PubMed:32538779"
FT MUTAGEN 45
FT /note="S->A: In AAA mutant; strongly decreased nucleosome-
FT binding; when associated with 206-A--A-208."
FT /evidence="ECO:0000269|PubMed:33067423"
FT MUTAGEN 56
FT /note="S->Y: Abolished NAD-dependent protein deacetylase,
FT defatty-acylase and mono-ADP-ribosyltransferase
FT activities."
FT /evidence="ECO:0000269|PubMed:21680843,
FT ECO:0000269|PubMed:22753495, ECO:0000269|PubMed:27322069,
FT ECO:0000269|PubMed:32789493"
FT MUTAGEN 60
FT /note="G->A: Does not affect the NAD-dependent protein
FT defatty-acylase activity. Abolished NAD-dependent protein
FT deacetylase and mono-ADP-ribosyltransferase activities."
FT /evidence="ECO:0000269|PubMed:21680843,
FT ECO:0000269|PubMed:22753495, ECO:0000269|PubMed:27322069,
FT ECO:0000269|PubMed:28406396"
FT MUTAGEN 65
FT /note="R->A: Does not affect the mono-ADP-
FT ribosyltransferase activity. Abolished NAD-dependent
FT protein deacetylase and defatty-acylase activities."
FT /evidence="ECO:0000269|PubMed:21680843,
FT ECO:0000269|PubMed:22753495, ECO:0000269|PubMed:27322069"
FT MUTAGEN 82
FT /note="F->A,E: Reduced MDL-800 and MDL-801 compounds-
FT binding."
FT /evidence="ECO:0000269|PubMed:30374165"
FT MUTAGEN 86
FT /note="F->E: Strongly reduced MDL-800 and MDL-801
FT compounds-binding."
FT /evidence="ECO:0000269|PubMed:30374165"
FT MUTAGEN 86
FT /note="F->Q: Slightly reduced MDL-800 and MDL-801
FT compounds-binding."
FT /evidence="ECO:0000269|PubMed:30374165"
FT MUTAGEN 133
FT /note="H->Y: Abolished NAD-dependent protein deacetylase,
FT deacylase and mono-ADP-ribosyltransferase activities.
FT Impaired ability to recognize and bind double-strand breaks
FT (DSBs) sites."
FT /evidence="ECO:0000269|PubMed:18337721,
FT ECO:0000269|PubMed:23142079, ECO:0000269|PubMed:23552949,
FT ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:23911928,
FT ECO:0000269|PubMed:26787900, ECO:0000269|PubMed:27043296,
FT ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:28406396,
FT ECO:0000269|PubMed:29474172, ECO:0000269|PubMed:31995034,
FT ECO:0000269|PubMed:32538779, ECO:0000269|PubMed:32789493"
FT MUTAGEN 170
FT /note="K->R: Decreased ubiquitination."
FT /evidence="ECO:0000269|PubMed:24043303"
FT MUTAGEN 206..208
FT /note="Missing: In AAA mutant; strongly decreased
FT nucleosome-binding; when associated with A-45."
FT /evidence="ECO:0000269|PubMed:33067423"
FT MUTAGEN 294
FT /note="T->A: Does not affect ability to promote DNA
FT repair."
FT /evidence="ECO:0000269|PubMed:27568560"
FT MUTAGEN 296..300
FT /note="KLEPK->RLEPR: In 4KR mutant; abolished sumoylation,
FT leading to increased H3K56ac; when associated with R-316
FT and R-332."
FT /evidence="ECO:0000269|PubMed:26898756"
FT MUTAGEN 303
FT /note="S->A: Does not affect ability to promote DNA
FT repair."
FT /evidence="ECO:0000269|PubMed:27568560"
FT MUTAGEN 316
FT /note="K->R: In 4KR mutant; abolished sumoylation, leading
FT to increased H3K56ac; when associated with 296-R--R-300 and
FT R-332."
FT /evidence="ECO:0000269|PubMed:26898756"
FT MUTAGEN 330
FT /note="S->A: Does not affect ability to promote DNA
FT repair."
FT /evidence="ECO:0000269|PubMed:27568560"
FT MUTAGEN 332
FT /note="K->R: In 4KR mutant; abolished sumoylation, leading
FT to increased H3K56ac; when associated with 296-R--R-300 and
FT R-316."
FT /evidence="ECO:0000269|PubMed:26898756"
FT MUTAGEN 338
FT /note="S->A: Does not affect ability to promote DNA
FT repair."
FT /evidence="ECO:0000269|PubMed:27568560"
FT CONFLICT 42
FT /note="W -> R (in Ref. 3; CAG33481)"
FT /evidence="ECO:0000305"
FT CONFLICT 249
FT /note="H -> Y (in Ref. 6; AAH04218)"
FT /evidence="ECO:0000305"
FT CONFLICT 267
FT /note="K -> E (in Ref. 1; AAF43432)"
FT /evidence="ECO:0000305"
FT HELIX 5..9
FT /evidence="ECO:0007829|PDB:6XV6"
FT TURN 10..12
FT /evidence="ECO:0007829|PDB:6XV6"
FT HELIX 27..43
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 45..51
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 53..55
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 57..59
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 64..66
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 70..75
FT /evidence="ECO:0007829|PDB:6HOY"
FT TURN 86..88
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 93..103
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 108..112
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 118..121
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 122..125
FT /evidence="ECO:0007829|PDB:3PKI"
FT HELIX 126..128
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 129..131
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 138..141
FT /evidence="ECO:0007829|PDB:6HOY"
FT TURN 142..144
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 147..149
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 161..165
FT /evidence="ECO:0007829|PDB:6HOY"
FT TURN 171..174
FT /evidence="ECO:0007829|PDB:5X16"
FT STRAND 180..183
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 188..190
FT /evidence="ECO:0007829|PDB:3PKJ"
FT HELIX 194..206
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 208..214
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 222..224
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 225..228
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 229..233
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 235..239
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 247..249
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 251..254
FT /evidence="ECO:0007829|PDB:6HOY"
FT HELIX 258..269
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 278..280
FT /evidence="ECO:0007829|PDB:6HOY"
FT STRAND 282..284
FT /evidence="ECO:0007829|PDB:6XV1"
SQ SEQUENCE 355 AA; 39119 MW; 0C86AAC497130BBF CRC64;
MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL VWQSSSVVFH TGAGISTASG
IPDFRGPHGV WTMEERGLAP KFDTTFESAR PTQTHMALVQ LERVGLLRFL VSQNVDGLHV
RSGFPRDKLA ELHGNMFVEE CAKCKTQYVR DTVVGTMGLK ATGRLCTVAK ARGLRACRGE
LRDTILDWED SLPDRDLALA DEASRNADLS ITLGTSLQIR PSGNLPLATK RRGGRLVIVN
LQPTKHDRHA DLRIHGYVDE VMTRLMKHLG LEIPAWDGPR VLERALPPLP RPPTPKLEPK
EESPTRINGS IPAGPKQEPC AQHNGSEPAS PKRERPTSPA PHRPPKRVKA KAVPS
