Q8N6T7 (SIR6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
NAD-dependent protein deacetylase sirtuin-6
EC=3.5.1.-

Alternative name(s):
Regulatory protein SIR2 homolog 6
SIR2-like protein 6

Gene names

Name:	SIRT6
Synonyms:	SIR2L6

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	355 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	NAD-dependent protein deacetylase. Has deacetylase activity towards histone H3K9Ac and H3K56Ac. Modulates acetylation of histone H3 in telomeric chromatin during the S-phase of the cell cycle. Deacetylates histone H3K9Ac at NF-kappa-B target promoters and may down-regulate the expression of a subset of NF-kappa-B target genes. Acts as a corepressor of the transcription factor HIF1A to control the expression of multiple glycolytic genes to regulate glucose homeostasis. Required for genomic stability. Regulates the production of TNF protein. Has a role in the regulation of life span By similarity. 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. On DNA damage, promotes DNA end resection via deacetylation of RBBP8. Has very weak deacetylase activity and can bind NAD+ in the absence of acetylated substrate. Ref.8 Ref.10 Ref.11 Ref.12 Ref.14
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. Interacts with RBBP8; the interaction deacetylates RBBP8. Ref.10 Ref.12
Subcellular location	Nucleus › nucleoplasm. Note: Predominantly nuclear. Associated with telomeric heterochromatin regions. Ref.7 Ref.8 Ref.10
Miscellaneous	The reported ADP-ribosyltransferase activity of sirtuins is likely some inefficient side reaction of the deacetylase activity and may not be physiologically relevant By similarity.
Sequence similarities	Belongs to the sirtuin family. Class IV subfamily. 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: Erroneous translation. Wrong choice of CCDS.

Ontologies

Keywords
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	Metal-binding NAD Zinc
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	protein ADP-ribosylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of double-strand break repair via homologous recombination Inferred from direct assay Ref.10. Source: UniProtKB
Cellular_component	nuclear telomeric heterochromatin Inferred from direct assay Ref.8. Source: UniProtKB nucleoplasm Inferred from direct assay Ref.7. Source: UniProtKB
Molecular_function	NAD(P)+-protein-arginine ADP-ribosyltransferase activity Inferred from sequence or structural similarity. Source: UniProtKB NAD+ ADP-ribosyltransferase activity Traceable author statement PubMed 17456799. Source: BHF-UCL NAD+ binding Inferred from sequence or structural similarity. Source: UniProtKB NAD-dependent histone deacetylase activity (H3-K9 specific) Inferred from direct assay Ref.8. Source: UniProtKB zinc ion binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RELA	Q04206	4	EBI-712415,EBI-73886

Alternative products

This entry describes 2 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.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 355

355

NAD-dependent protein deacetylase sirtuin-6

PRO_0000110269

Regions

Domain

35 – 274

240

Deacetylase sirtuin-type

Nucleotide binding

52 – 71

20

NAD

Nucleotide binding

113 – 116

4

NAD

Nucleotide binding

214 – 216

3

NAD

Nucleotide binding

240 – 242

3

NAD

Compositional bias

287 – 345

59

Pro-rich

Sites

Active site

133

1

Proton acceptor

Metal binding

141

1

Zinc

Metal binding

144

1

Zinc

Metal binding

166

1

Zinc

Metal binding

177

1

Zinc

Binding site

258

1

NAD; via amide nitrogen

Amino acid modifications

Modified residue

303

1

Phosphoserine Ref.9

Modified residue

330

1

Phosphoserine Ref.13

Natural variations

Alternative sequence

179 – 205

27

Missing in isoform 2.

VSP_008733

Natural variant

46

1

S → N. Ref.2 Ref.5 Ref.6
Corresponds to variant rs352493 [ dbSNP | Ensembl ].

VAR_017154

Experimental info

Mutagenesis

133

1

H → Y: Loss of enzyme activity. Abolishes RBBP8 deacetylation and promotion of DNA end resection after DNA damage. Ref.8 Ref.12

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

Secondary structure

1

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355

Helix Strand Turn

Details...

Helix

27 – 43

17

Beta strand

47 – 51

5

Helix

53 – 55

3

Helix

57 – 59

3

Beta strand

64 – 66

3

Helix

70 – 74

5

Turn

75 – 77

3

Turn

86 – 88

3

Helix

93 – 103

11

Beta strand

109 – 112

4

Helix

118 – 121

4

Beta strand

122 – 125

4

Helix

126 – 128

3

Beta strand

129 – 131

3

Beta strand

138 – 141

4

Turn

142 – 144

3

Beta strand

147 – 149

3

Beta strand

161 – 165

5

Beta strand

180 – 183

4

Beta strand

188 – 190

3

Helix

194 – 205

12

Beta strand

208 – 214

7

Helix

222 – 224

3

Helix

225 – 231

7

Beta strand

235 – 239

5

Helix

247 – 249

3

Beta strand

251 – 254

4

Helix

258 – 269

12

Beta strand

280 – 282

3

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 [UniParc]. 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

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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANT ASN-46. Tissue: Blood, Eye and Lung.
[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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-303, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"Human SIRT6 promotes DNA end resection through CtIP deacetylation." Kaidi A., Weinert B.T., Choudhary C., Jackson S.P. Science 329:1348-1353(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH RBBP8, MUTAGENESIS OF HIS-133.
[13]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-330, MASS SPECTROMETRY.
[14]	"Structure and biochemical functions of SIRT6." Pan P.W., Feldman J.L., Devries M.K., Dong A., Edwards A.M., Denu J.M. J. Biol. Chem. 286:14575-14587(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 2-318 IN COMPLEX WITH ZINC AND ADP-RIBOSE, FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.
BC004218 mRNA. Translation: AAH04218.1. Sequence problems.
BC005026 mRNA. Translation: AAH05026.1.
BC028220 mRNA. Translation: AAH28220.1.

IPI

IPI00383640.
IPI00396170.
IPI00556638.

RefSeq

NP_001180214.1. NM_001193285.1.
NP_057623.2. NM_016539.2.

UniGene

Hs.423756.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3K35	X-ray	2.00	A/B/C/D/E/F	2-318	[»]
3PKI	X-ray	2.04	A/B/C/D/E/F	2-355	[»]
3PKJ	X-ray	2.12	A/B/C/D/E/F	2-355	[»]

ProteinModelPortal

Q8N6T7.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-47346N.

IntAct

Q8N6T7. 4 interactions.

MINT

MINT-1374731.

PTM databases

PhosphoSite

Q8N6T7.

Polymorphism databases

DMDM

38258612.

Proteomic databases

PaxDb

Q8N6T7.

PRIDE

Q8N6T7.

Protocols and materials databases

DNASU

51548.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000305232; ENSP00000305310; ENSG00000077463.
ENST00000337491; ENSP00000337332; ENSG00000077463.

GeneID

51548.

KEGG

hsa:51548.

UCSC

uc002lzo.3. human.
uc002lzq.3. human.
uc002lzr.3. human.

Organism-specific databases

CTD

51548.

GeneCards

GC19M004125.

H-InvDB

HIX0014654.

HGNC

HGNC:14934. SIRT6.

MIM

606211. gene.

neXtProt

NX_Q8N6T7.

PharmGKB

PA37939.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0846.

HOVERGEN

HBG060028.

InParanoid

Q8N6T7.

KO

K11416.

OMA

TKHDRQA.

PhylomeDB

Q8N6T7.

Enzyme and pathway databases

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. Sirtuin.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]

PANTHER

PTHR11085. PTHR11085. 1 hit.

Pfam

PF02146. SIR2. 2 hits.
[Graphical view]

PROSITE

PS50305. SIRTUIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

SIRT6. human.

EvolutionaryTrace

Q8N6T7.

GenomeRNAi

51548.

NextBio

55327.

SOURCE

Search...

Entry information

Entry name

SIR6_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:	May 1, 2013
This is version 106 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.