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Q8N6T7 (SIR6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 116. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length355 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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.11 Ref.12 Ref.13 Ref.15

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.11 Ref.13

Subcellular location

Nucleusnucleoplasm. Note: Predominantly nuclear. Associated with telomeric heterochromatin regions. Ref.7 Ref.8 Ref.11

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 componentNucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   LigandMetal-binding
NAD
Zinc
   Molecular functionHydrolase
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processhistone H3 deacetylation

Inferred from direct assay Ref.8. Source: GOC

histone deacetylation

Inferred from sequence or structural similarity. Source: GOC

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.11. Source: UniProtKB

   Cellular_componentnuclear telomeric heterochromatin

Inferred from direct assay Ref.8. Source: UniProtKB

nucleoplasm

Inferred from direct assay Ref.7. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionNAD(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

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

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.10
Chain2 – 355354NAD-dependent protein deacetylase sirtuin-6
PRO_0000110269

Regions

Domain35 – 274240Deacetylase sirtuin-type
Nucleotide binding52 – 7120NAD
Nucleotide binding113 – 1164NAD
Nucleotide binding214 – 2163NAD
Nucleotide binding240 – 2423NAD
Compositional bias287 – 34559Pro-rich

Sites

Active site1331Proton acceptor
Metal binding1411Zinc
Metal binding1441Zinc
Metal binding1661Zinc
Metal binding1771Zinc
Binding site2581NAD; via amide nitrogen

Amino acid modifications

Modified residue21N-acetylserine Ref.10
Modified residue3031Phosphoserine Ref.9
Modified residue3301Phosphoserine Ref.14

Natural variations

Alternative sequence179 – 20527Missing in isoform 2.
VSP_008733
Natural variant461S → N. Ref.2 Ref.5 Ref.6
Corresponds to variant rs352493 [ dbSNP | Ensembl ].
VAR_017154

Experimental info

Mutagenesis1331H → Y: Loss of enzyme activity. Abolishes RBBP8 deacetylation and promotion of DNA end resection after DNA damage. Ref.8 Ref.13
Sequence conflict421W → R in CAG33481. Ref.3
Sequence conflict2491H → Y in AAH04218. Ref.6
Sequence conflict2671K → E in AAF43432. Ref.1

Secondary structure

......................................................... 355
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 31, 2003. Version 2.
Checksum: 0C86AAC497130BBF

FASTA35539,119
        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 

« Hide

Isoform 2 [UniParc].

Checksum: 503805C898FD7769
Show »

FASTA32836,065

References

« Hide '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. expand/collapse author list , 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. expand/collapse author list , 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. expand/collapse author list , 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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[10]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
[11]"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.
[12]"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.
[13]"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.
[14]"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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]"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.
RefSeqNP_001180214.1. NM_001193285.1.
NP_057623.2. NM_016539.2.
UniGeneHs.423756.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3K35X-ray2.00A/B/C/D/E/F2-318[»]
3PKIX-ray2.04A/B/C/D/E/F2-355[»]
3PKJX-ray2.12A/B/C/D/E/F2-355[»]
3ZG6X-ray2.20A1-296[»]
ProteinModelPortalQ8N6T7.
SMRQ8N6T7. Positions 13-285.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid119603. 17 interactions.
DIPDIP-47346N.
IntActQ8N6T7. 7 interactions.
MINTMINT-1374731.

Chemistry

ChEMBLCHEMBL2163182.

PTM databases

PhosphoSiteQ8N6T7.

Polymorphism databases

DMDM38258612.

Proteomic databases

PaxDbQ8N6T7.
PRIDEQ8N6T7.

Protocols and materials databases

DNASU51548.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000305232; ENSP00000305310; ENSG00000077463. [Q8N6T7-2]
ENST00000337491; ENSP00000337332; ENSG00000077463. [Q8N6T7-1]
GeneID51548.
KEGGhsa:51548.
UCSCuc002lzo.3. human. [Q8N6T7-1]
uc002lzq.3. human. [Q8N6T7-2]

Organism-specific databases

CTD51548.
GeneCardsGC19M004125.
H-InvDBHIX0014654.
HGNCHGNC:14934. SIRT6.
MIM606211. gene.
neXtProtNX_Q8N6T7.
PharmGKBPA37939.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0846.
HOVERGENHBG060028.
InParanoidQ8N6T7.
KOK11416.
OMATKHDRQA.
PhylomeDBQ8N6T7.
TreeFamTF106184.

Gene expression databases

ArrayExpressQ8N6T7.
BgeeQ8N6T7.
GenevestigatorQ8N6T7.

Family and domain databases

InterProIPR003000. Sirtuin.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERPTHR11085. PTHR11085. 1 hit.
PfamPF02146. SIR2. 2 hits.
[Graphical view]
PROSITEPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSSIRT6. human.
EvolutionaryTraceQ8N6T7.
GeneWikiSIRT6.
GenomeRNAi51548.
NextBio55327.
PROQ8N6T7.
SOURCESearch...

Entry information

Entry nameSIR6_HUMAN
AccessionPrimary (citable) accession number: Q8N6T7
Secondary accession number(s): B2RCD0 expand/collapse secondary AC list , 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: April 16, 2014
This is version 116 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 19

Human chromosome 19: entries, gene names and cross-references to MIM