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Protein

NAD-dependent protein deacetylase sirtuin-6

Gene

Sirt6

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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. 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. 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 (By similarity). 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. Required for normal IGF1 serum levels and normal glucose homeostasis. Modulates cellular senescence and apoptosis. Regulates the production of TNF protein. Has a role in the regulation of life span in male mice, but not in female mice.By similarity7 Publications

Catalytic activityi

NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein.PROSITE-ProRule annotation1 Publication

Cofactori

Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei133 – 1331Proton acceptorPROSITE-ProRule annotation
Metal bindingi141 – 1411ZincPROSITE-ProRule annotation
Metal bindingi144 – 1441ZincPROSITE-ProRule annotation
Metal bindingi166 – 1661ZincPROSITE-ProRule annotation
Metal bindingi177 – 1771ZincPROSITE-ProRule annotation
Binding sitei258 – 2581NAD; via amide nitrogenBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi52 – 7120NADBy similarityAdd
BLAST
Nucleotide bindingi113 – 1164NADBy similarity
Nucleotide bindingi214 – 2163NADBy similarity
Nucleotide bindingi240 – 2423NADBy similarity

GO - Molecular functioni

  • chromatin binding Source: MGI
  • NAD(P)+-protein-arginine ADP-ribosyltransferase activity Source: UniProtKB
  • NAD+ binding Source: UniProtKB
  • NAD-dependent histone deacetylase activity Source: UniProtKB
  • NAD-dependent histone deacetylase activity (H3-K9 specific) Source: UniProtKB
  • transcription corepressor activity Source: CACAO
  • zinc ion binding Source: UniProtKB

GO - Biological processi

  • base-excision repair Source: CACAO
  • glucose homeostasis Source: CACAO
  • histone H3-K9 deacetylation Source: MGI
  • histone H3-K9 modification Source: MGI
  • negative regulation of cell proliferation Source: CACAO
  • negative regulation of glucose import Source: CACAO
  • negative regulation of glycolytic process Source: CACAO
  • negative regulation of transcription, DNA-templated Source: CACAO
  • positive regulation of fibroblast proliferation Source: CACAO
  • positive regulation of stem cell proliferation Source: CACAO
  • post-embryonic cardiac muscle cell growth involved in heart morphogenesis Source: Ensembl
  • protein ADP-ribosylation Source: UniProtKB
  • protein destabilization Source: CACAO
  • regulation of double-strand break repair via homologous recombination Source: UniProtKB
  • response to nutrient levels Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Ligandi

Metal-binding, NAD, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-5693607. Processing of DNA double-strand break ends.

Names & Taxonomyi

Protein namesi
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 namesi
Name:Sirt6
Synonyms:Sir2l6
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1354161. Sirt6.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: Ensembl
  • nuclear telomeric heterochromatin Source: UniProtKB
  • nucleoplasm Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Impaired genomic stability. No visible phenotype at birth. Normal development during the first two weeks, except for reduced growth. At about three weeks after birth, the mice undergo compound degenerative processes, fail to thrive, and die about 24 days after birth. They exhibit acute loss of subcutaneous fat, lordokyphosis, erosion of the superficial colon epithelium, severe lymphopenia, osteopenia, severely reduced IGF1 serum levels and extremely low serum glucose levels.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi56 – 561S → A: Loss of activity. 1 Publication
Mutagenesisi133 – 1331H → Y: Loss of activity. 2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 334333NAD-dependent protein deacetylase sirtuin-6PRO_0000110270Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineBy similarity

Keywords - PTMi

Acetylation

Proteomic databases

EPDiP59941.
MaxQBiP59941.
PaxDbiP59941.
PRIDEiP59941.

PTM databases

PhosphoSiteiP59941.

Expressioni

Tissue specificityi

Highest levels are found in muscle, thymus, spleen, brain and heart (at protein level).2 Publications

Developmental stagei

Expression peaks at embryonic day 11 and persists into adulthood.1 Publication

Gene expression databases

BgeeiP59941.
ExpressionAtlasiP59941. baseline and differential.
GenevisibleiP59941. MM.

Interactioni

Subunit structurei

Interacts with RBBP8; the interaction deacetylates RBBP8 (By similarity). Interacts with RELA.By similarity1 Publication

Protein-protein interaction databases

BioGridi206064. 1 interaction.
IntActiP59941. 1 interaction.
STRINGi10090.ENSMUSP00000048971.

Structurei

3D structure databases

ProteinModelPortaliP59941.
SMRiP59941. Positions 13-285.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini35 – 274240Deacetylase sirtuin-typePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Belongs to the sirtuin family. Class IV subfamily.Curated
Contains 1 deacetylase sirtuin-type domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG1905. Eukaryota.
COG0846. LUCA.
GeneTreeiENSGT00530000063706.
HOGENOMiHOG000231240.
HOVERGENiHBG060028.
InParanoidiP59941.
KOiK11416.
OMAiNVLDWEH.
PhylomeDBiP59941.
TreeFamiTF106184.

Family and domain databases

Gene3Di3.40.50.1220. 2 hits.
InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERiPTHR11085. PTHR11085. 1 hit.
PfamiPF02146. SIR2. 2 hits.
[Graphical view]
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiPS50305. SIRTUIN. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P59941-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL MWQSSSVVFH
60 70 80 90 100
TGAGISTASG IPDFRGPHGV WTMEERGLAP KFDTTFENAR PSKTHMALVQ
110 120 130 140 150
LERMGFLSFL VSQNVDGLHV RSGFPRDKLA ELHGNMFVEE CPKCKTQYVR
160 170 180 190 200
DTVVGTMGLK ATGRLCTVAK TRGLRACRGE LRDTILDWED SLPDRDLMLA
210 220 230 240 250
DEASRTADLS VTLGTSLQIR PSGNLPLATK RRGGRLVIVN LQPTKHDRQA
260 270 280 290 300
DLRIHGYVDE VMCRLMKHLG LEIPAWDGPC VLDKALPPLP RPVALKAEPP
310 320 330
VHLNGAVHVS YKSKPNSPIL HRPPKRVKTE AAPS
Length:334
Mass (Da):36,920
Last modified:October 31, 2003 - v1
Checksum:i75FD950B42D68A1A
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC052763 mRNA. Translation: AAH52763.1.
CCDSiCCDS24066.1.
RefSeqiNP_853617.1. NM_181586.3.
UniGeneiMm.131825.
Mm.25643.

Genome annotation databases

EnsembliENSMUST00000042923; ENSMUSP00000048971; ENSMUSG00000034748.
GeneIDi50721.
KEGGimmu:50721.
UCSCiuc007giy.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC052763 mRNA. Translation: AAH52763.1.
CCDSiCCDS24066.1.
RefSeqiNP_853617.1. NM_181586.3.
UniGeneiMm.131825.
Mm.25643.

3D structure databases

ProteinModelPortaliP59941.
SMRiP59941. Positions 13-285.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi206064. 1 interaction.
IntActiP59941. 1 interaction.
STRINGi10090.ENSMUSP00000048971.

PTM databases

PhosphoSiteiP59941.

Proteomic databases

EPDiP59941.
MaxQBiP59941.
PaxDbiP59941.
PRIDEiP59941.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000042923; ENSMUSP00000048971; ENSMUSG00000034748.
GeneIDi50721.
KEGGimmu:50721.
UCSCiuc007giy.2. mouse.

Organism-specific databases

CTDi51548.
MGIiMGI:1354161. Sirt6.

Phylogenomic databases

eggNOGiKOG1905. Eukaryota.
COG0846. LUCA.
GeneTreeiENSGT00530000063706.
HOGENOMiHOG000231240.
HOVERGENiHBG060028.
InParanoidiP59941.
KOiK11416.
OMAiNVLDWEH.
PhylomeDBiP59941.
TreeFamiTF106184.

Enzyme and pathway databases

ReactomeiR-MMU-5693607. Processing of DNA double-strand break ends.

Miscellaneous databases

ChiTaRSiSirt6. mouse.
PROiP59941.
SOURCEiSearch...

Gene expression databases

BgeeiP59941.
ExpressionAtlasiP59941. baseline and differential.
GenevisibleiP59941. MM.

Family and domain databases

Gene3Di3.40.50.1220. 2 hits.
InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERiPTHR11085. PTHR11085. 1 hit.
PfamiPF02146. SIR2. 2 hits.
[Graphical view]
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "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].
    Tissue: Limb.
  2. "Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase."
    Liszt G., Ford E., Kurtev M., Guarente L.
    J. Biol. Chem. 280:21313-21320(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, MUTAGENESIS OF SER-56 AND HIS-133.
  3. Cited for: DISRUPTION PHENOTYPE, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
  4. "Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and 32P-NAD."
    Du J., Jiang H., Lin H.
    Biochemistry 48:2878-2890(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  5. "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.
  6. "The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability."
    Yang B., Zwaans B.M.M., Eckersdorff M., Lombard D.B.
    Cell Cycle 8:2662-2663(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF HIS-133.
  7. "Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner."
    Van Gool F., Galli M., Gueydan C., Kruys V., Prevot P.P., Bedalov A., Mostoslavsky R., Alt F.W., De Smedt T., Leo O.
    Nat. Med. 15:206-210(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. Cited for: FUNCTION IN REGULATION OF GLUCOSE HOMEOSTASIS.
  9. Cited for: FUNCTION IN REGULATION OF LIFE SPAN.

Entry informationi

Entry nameiSIR6_MOUSE
AccessioniPrimary (citable) accession number: P59941
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 31, 2003
Last modified: June 8, 2016
This is version 110 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

The reported ADP-ribosyltransferase activity of sirtuins is likely some inefficient side reaction of the deacetylase activity and may not be physiologically relevant.1 Publication

Caution

Was originally thought to be a protein ADP-ribosyltransferase.1 Publication

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.