Reviewed, UniProtKB/Swiss-Prot Q8N6T7 (SIRT6_HUMAN)

Names and origin

Protein names

Recommended name:
    NAD-dependent deacetylase sirtuin-6
    EC=3.5.1.-
Alternative name(s):
    SIR2-like protein 6

Gene names

Name:	SIRT6
Synonyms:	SIR2L6

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	355 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	NAD-dependent protein deacetylase. Has deacetylase activity towards 'Lys-9' and 'Lys-56' of histone H3. Modulates acetylation of histone H3 in telomeric chromatin during the S-phase of the cell cycle. Deacetylates 'Lys-9' of histone H3 at NF-kappa-B target promoters and may down-regulate the expression of a subset of NF-kappa-B target genes. Deacetylation of nucleosomes interferes with RELA binding to target DNA. May be required for the association of WRN with telomeres during S-phase and for normal telomere maintenance. Required for genomic stability. Required for normal IGF1 serum levels and normal glucose homeostasis. Modulates cellular senescence and apoptosis. Regulates the production of TNF protein By similarity.
Catalytic activity	NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein. Ref.8
Cofactor	Binds 1 zinc ion per subunit By similarity.
Subunit structure	Interacts with RELA. Ref.10
Subcellular location	Nucleus › nucleoplasm. Note: Predominantly nuclear. Associated with telomeric heterochromatin regions. Ref.8 Ref.10 Ref.7
Sequence similarities	Belongs to the sirtuin family. Contains 1 deacetylase sirtuin-type domain.
Sequence caution	The sequence AAC34468.1 differs from that shown. Reason: Erroneous gene model prediction. The sequence AAD15478.1 differs from that shown. Reason: Erroneous gene model prediction. The sequence AAH04218.1 differs from that shown. Reason: Frameshift at position 23.

Ontologies

Keywords
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	Metal-binding NAD Zinc
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	chromatin silencing Inferred from electronic annotation. Source: InterPro protein amino acid ADP-ribosylation Inferred from sequence or structural similarity. Source: UniProtKB protein amino acid deacetylation Inferred from electronic annotation. Source: InterPro
Cellular component	nuclear telomeric heterochromatin Ref.8 Inferred from direct assay. Source: UniProtKB nucleoplasm Ref.7 Inferred from direct assay. Source: UniProtKB
Molecular function	NAD binding Inferred from electronic annotation. Source: InterPro NAD(P)+-protein-arginine ADP-ribosyltransferase activity Inferred from sequence or structural similarity. Source: UniProtKB NAD+ ADP-ribosyltransferase activity Traceable author statement. Source: UniProtKB NAD-dependent histone deacetylase activity (H3-K9 specific) Ref.8 Inferred from direct assay. Source: UniProtKB protein binding Ref.10 Inferred from physical interaction. Source: IntAct zinc ion binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RELA	Q04206	3	EBI-712415,EBI-73886

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8N6T7-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q8N6T7-2)

The sequence of this isoform differs from the canonical sequence as follows:
     179-205: Missing.

Note: No experimental confirmation available.

Isoform 3 (identifier: Q8N6T7-3)

The sequence of this isoform differs from the canonical sequence as follows:
     65-125: Missing.
     206-248: NADLSITLGT...VNLQPTKHDR → SGPAGTCRWL...SASMATLTRS
     249-355: Missing.

Note: No experimental confirmation available.

Isoform 4 (identifier: Q8N6T7-4)

The sequence of this isoform differs from the canonical sequence as follows:
     23-64: Missing.
     179-205: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 355	355	NAD-dependent deacetylase sirtuin-6		PRO_0000110269
Regions
	Domain	35 – 274	240	Deacetylase sirtuin-type
	Nucleotide binding	52 – 71	20	NAD By similarity
	Nucleotide binding	113 – 117	5	NAD By similarity
	Compositional bias	287 – 345	59	Pro-rich
Sites
	Active site	133	1	Proton acceptor
	Metal binding	141	1	Zinc By similarity
	Metal binding	144	1	Zinc By similarity
	Metal binding	166	1	Zinc By similarity
	Metal binding	177	1	Zinc By similarity
Amino acid modifications
	Modified residue	294	1	Phosphothreonine Ref.9
	Modified residue	303	1	Phosphoserine Ref.9
Natural variations
	Alternative sequence	23 – 64	42	Missing in isoform 4.		VSP_013659
	Alternative sequence	65 – 125	61	Missing in isoform 3.		VSP_008732
	Alternative sequence	179 – 205	27	Missing in isoform 2 and isoform 4.		VSP_008733
	Alternative sequence	206 – 248	43	NADLS…TKHDR → SGPAGTCRWLPSAGEAAWSS STCSPPSTTAMLTSASMATL TRS in isoform 3.		VSP_008734
	Alternative sequence	249 – 355	107	Missing in isoform 3.		VSP_008735
	Natural variant	46	1	S → N: dbSNP rs352493. Ref.2 Ref.5 Ref.6		VAR_017154
Experimental info
	Mutagenesis	133	1	H → Y: Loss of enzyme activity. Ref.8
	Sequence conflict	42	1	W → R in CAG33481. Ref.3
	Sequence conflict	249	1	H → Y in AAH04218. Ref.6
	Sequence conflict	267	1	K → E in AAF43432. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 31, 2003. Version 2. Checksum: 0C86AAC497130BBF	FASTA	355	39,119
	10 20 30 40 50 60 MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL VWQSSSVVFH TGAGISTASG 70 80 90 100 110 120 IPDFRGPHGV WTMEERGLAP KFDTTFESAR PTQTHMALVQ LERVGLLRFL VSQNVDGLHV 130 140 150 160 170 180 RSGFPRDKLA ELHGNMFVEE CAKCKTQYVR DTVVGTMGLK ATGRLCTVAK ARGLRACRGE 190 200 210 220 230 240 LRDTILDWED SLPDRDLALA DEASRNADLS ITLGTSLQIR PSGNLPLATK RRGGRLVIVN 250 260 270 280 290 300 LQPTKHDRHA DLRIHGYVDE VMTRLMKHLG LEIPAWDGPR VLERALPPLP RPPTPKLEPK 310 320 330 340 350 EESPTRINGS IPAGPKQEPC AQHNGSEPAS PKRERPTSPA PHRPPKRVKA KAVPS
	Isoform 2. Checksum: 503805C898FD7769	FASTA	328	36,065
	10 20 30 40 50 60 MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL VWQSSSVVFH TGAGISTASG 70 80 90 100 110 120 IPDFRGPHGV WTMEERGLAP KFDTTFESAR PTQTHMALVQ LERVGLLRFL VSQNVDGLHV 130 140 150 160 170 180 RSGFPRDKLA ELHGNMFVEE CAKCKTQYVR DTVVGTMGLK ATGRLCTVAK ARGLRACRNA 190 200 210 220 230 240 DLSITLGTSL QIRPSGNLPL ATKRRGGRLV IVNLQPTKHD RHADLRIHGY VDEVMTRLMK 250 260 270 280 290 300 HLGLEIPAWD GPRVLERALP PLPRPPTPKL EPKEESPTRI NGSIPAGPKQ EPCAQHNGSE 310 320 PASPKRERPT SPAPHRPPKR VKAKAVPS
	Isoform 3. Checksum: 7410BAB73DB086B2	FASTA	187	20,078
	10 20 30 40 50 60 MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL VWQSSSVVFH TGAGISTASG 70 80 90 100 110 120 IPDFRDKLAE LHGNMFVEEC AKCKTQYVRD TVVGTMGLKA TGRLCTVAKA RGLRACRGEL 130 140 150 160 170 180 RDTILDWEDS LPDRDLALAD EASRSGPAGT CRWLPSAGEA AWSSSTCSPP STTAMLTSAS MATLTRS
	Isoform 4. Checksum: 792F5F783F4B9F83	FASTA	286	31,409
	10 20 30 40 50 60 MSVNYAAGLS PYADKGKCGL PERGPHGVWT MEERGLAPKF DTTFESARPT QTHMALVQLE 70 80 90 100 110 120 RVGLLRFLVS QNVDGLHVRS GFPRDKLAEL HGNMFVEECA KCKTQYVRDT VVGTMGLKAT 130 140 150 160 170 180 GRLCTVAKAR GLRACRNADL SITLGTSLQI RPSGNLPLAT KRRGGRLVIV NLQPTKHDRH 190 200 210 220 230 240 ADLRIHGYVD EVMTRLMKHL GLEIPAWDGP RVLERALPPL PRPPTPKLEP KEESPTRING 250 260 270 280 SIPAGPKQEP CAQHNGSEPA SPKRERPTSP APHRPPKRVK AKAVPS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Phylogenetic classification of prokaryotic and eukaryotic Sir-2 like proteins." Frye R.A. Biochem. Biophys. Res. Commun. 273:793-798(2000) [PubMed: 10873683] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Spleen.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ASN-46. Tissue: Heart and Teratocarcinoma.
[3]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[4]	"The DNA sequence and biology of human chromosome 19." Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M. Nature 428:529-535(2004) [PubMed: 15057824] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT ASN-46.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 3 AND 4), VARIANT ASN-46. Tissue: Blood, Eye, Lung and Placenta.
[7]	"Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins." Michishita E., Park J.Y., Burneskis J.M., Barrett J.C., Horikawa I. Mol. Biol. Cell 16:4623-4635(2005) [PubMed: 16079181] [Abstract] Cited for: SUBCELLULAR LOCATION.
[8]	"SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin." Michishita E., McCord R.A., Berber E., Kioi M., Padilla-Nash H., Damian M., Cheung P., Kusumoto R., Kawahara T.L.A., Barrett J.C., Chang H.Y., Bohr V.A., Ried T., Gozani O., Chua K.F. Nature 452:492-496(2008) [PubMed: 18337721] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-133, SUBCELLULAR LOCATION.
[9]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-294 AND SER-303, MASS SPECTROMETRY.
[10]	"SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span." Kawahara T.L.A., Michishita E., Adler A.S., Damian M., Berber E., Lin M., McCord R.A., Ongaigui K.C.L., Boxer L.D., Chang H.Y., Chua K.F. Cell 136:62-74(2009) [PubMed: 19135889] [Abstract] Cited for: FUNCTION, INTERACTION WITH RELA, SUBCELLULAR LOCATION.
[11]	"Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6." Michishita E., McCord R.A., Boxer L.D., Barber M.F., Hong T., Gozani O., Chua K.F. Cell Cycle 8:2664-2666(2009) [PubMed: 19625767] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF233396 mRNA. Translation: AAF43432.1. AK074810 mRNA. Translation: BAC11222.1. AK315048 mRNA. Translation: BAG37527.1. CR457200 mRNA. Translation: CAG33481.1. AC005620 Genomic DNA. Translation: AAC34468.1. Sequence problems. AC006930 Genomic DNA. Translation: AAD15478.1. Sequence problems. CH471139 Genomic DNA. Translation: EAW69252.1. BC000090 mRNA. Translation: AAH00090.1. Different initiation. BC004218 mRNA. Translation: AAH04218.1. Frameshift. BC005026 mRNA. Translation: AAH05026.1. BC028220 mRNA. Translation: AAH28220.1.
IPI	IPI00332636. IPI00383640. IPI00396170. IPI00556638.
RefSeq	NP_057623.1.
UniGene	Hs.423756
3D structure databases
HSSP	HSSP built from PDB template 1ICI based on UniProtKB O28597.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8N6T7. 6 interactions.
STRING	Q8N6T7.
PTM databases
PhosphoSite	Q8N6T7.
Genome annotation databases
Ensembl	ENST00000269860; ENSP00000269860; ENSG00000077463; Homo sapiens. [Genome view] ENST00000305232; ENSP00000305310; ENSG00000077463; Homo sapiens. [Genome view] ENST00000337491; ENSP00000337332; ENSG00000077463; Homo sapiens. [Genome view] ENST00000381935; ENSP00000371360; ENSG00000077463; Homo sapiens. [Genome view]
GeneID	51548.
KEGG	hsa:51548.
UCSC	uc002lzn.1. human. uc002lzo.1. human. uc002lzq.1. human.
Organism-specific databases
CTD	51548.
GeneCards	GC19M004125.
H-InvDB	HIX0014654.
HGNC	HGNC:14934. SIRT6.
MIM	606211. gene.
PharmGKB	PA37939.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q8N6T7.
OMA	IPAWDGP.
Enzyme and pathway databases
BRENDA	2.4.2.31. 247.
Pathway_Interaction_DB	hdac_classi_pathway. Signaling events mediated by HDAC Class I.
Gene expression databases
ArrayExpress	Q8N6T7.
Bgee	Q8N6T7.
Genevestigator	Q8N6T7.
GermOnline	ENSG00000077463. Homo sapiens.
Family and domain databases
InterPro	IPR003000. NAD-dep_histone_deAcase_SIR2. [Graphical view]
PANTHER	PTHR11085. SIR2. 1 hit.
Pfam	PF02146. SIR2. 1 hit. [Graphical view]
PROSITE	PS50305. SIRTUIN. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	55327.
SOURCE	Search...

Entry information

Entry name

SIRT6_HUMAN

Accession

Primary (citable) accession number: Q8N6T7
Secondary accession number(s): B2RCD0 , O75291, Q6IAF5, Q6PK99, Q8NCD2, Q9BSI5, Q9BWP3, Q9NRC7, Q9UQD1

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 31, 2003
Last sequence update:	October 31, 2003
Last modified:	November 3, 2009
This is version 72 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.