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Protein

NAD-dependent protein deacetylase sirtuin-6

Gene

SIRT6

Organism
Homo sapiens (Human)
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. 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.By similarity5 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)DescriptionActionsGraphical viewLength
Active sitei133Proton acceptor1
Metal bindingi141ZincPROSITE-ProRule annotation1 Publication1
Metal bindingi144ZincPROSITE-ProRule annotation1 Publication1
Metal bindingi166ZincPROSITE-ProRule annotation1 Publication1
Metal bindingi177ZincPROSITE-ProRule annotation1 Publication1
Binding sitei258NAD; via amide nitrogen1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi52 – 71NADAdd BLAST20
Nucleotide bindingi113 – 116NAD4
Nucleotide bindingi214 – 216NAD3
Nucleotide bindingi240 – 242NAD3

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Ligandi

Metal-binding, NAD, Zinc

Enzyme and pathway databases

BioCyciZFISH:HS01247-MONOMER.
ReactomeiR-HSA-5693607. Processing of DNA double-strand break ends.
SIGNORiQ8N6T7.

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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:14934. 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

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi133H → Y: Loss of enzyme activity. Abolishes RBBP8 deacetylation and promotion of DNA end resection after DNA damage. 2 Publications1

Organism-specific databases

DisGeNETi51548.
OpenTargetsiENSG00000077463.
PharmGKBiPA37939.

Chemistry databases

ChEMBLiCHEMBL2163182.
GuidetoPHARMACOLOGYi2712.

Polymorphism and mutation databases

BioMutaiSIRT6.
DMDMi38258612.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00001102692 – 355NAD-dependent protein deacetylase sirtuin-6Add BLAST354

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1
Modified residuei10PhosphoserineCombined sources1
Modified residuei294PhosphothreonineCombined sources1
Modified residuei303PhosphoserineCombined sources1
Modified residuei330PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ8N6T7.
MaxQBiQ8N6T7.
PaxDbiQ8N6T7.
PeptideAtlasiQ8N6T7.
PRIDEiQ8N6T7.

PTM databases

iPTMnetiQ8N6T7.
PhosphoSitePlusiQ8N6T7.

Expressioni

Gene expression databases

BgeeiENSG00000077463.
ExpressionAtlasiQ8N6T7. baseline and differential.
GenevisibleiQ8N6T7. HS.

Organism-specific databases

HPAiHPA071776.

Interactioni

Subunit structurei

Interacts with RELA. Interacts with RBBP8; the interaction deacetylates RBBP8.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
MYCP011063EBI-712415,EBI-447544
RELAQ042064EBI-712415,EBI-73886

Protein-protein interaction databases

BioGridi119603. 176 interactors.
DIPiDIP-47346N.
IntActiQ8N6T7. 17 interactors.
MINTiMINT-1374731.
STRINGi9606.ENSP00000337332.

Chemistry databases

BindingDBiQ8N6T7.

Structurei

Secondary structure

1355
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni5 – 8Combined sources4
Helixi27 – 43Combined sources17
Beta strandi47 – 51Combined sources5
Helixi53 – 55Combined sources3
Helixi57 – 59Combined sources3
Beta strandi64 – 66Combined sources3
Helixi70 – 74Combined sources5
Turni75 – 77Combined sources3
Turni86 – 88Combined sources3
Helixi93 – 103Combined sources11
Beta strandi109 – 112Combined sources4
Helixi118 – 121Combined sources4
Beta strandi122 – 125Combined sources4
Helixi126 – 128Combined sources3
Beta strandi129 – 131Combined sources3
Beta strandi138 – 141Combined sources4
Turni142 – 144Combined sources3
Beta strandi147 – 149Combined sources3
Beta strandi161 – 165Combined sources5
Turni171 – 174Combined sources4
Beta strandi180 – 183Combined sources4
Beta strandi188 – 190Combined sources3
Helixi194 – 205Combined sources12
Beta strandi208 – 214Combined sources7
Helixi222 – 224Combined sources3
Helixi225 – 231Combined sources7
Beta strandi235 – 239Combined sources5
Helixi247 – 249Combined sources3
Beta strandi251 – 254Combined sources4
Helixi258 – 269Combined sources12
Beta strandi280 – 282Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3K35X-ray2.00A/B/C/D/E/F3-318[»]
3PKIX-ray2.04A/B/C/D/E/F2-355[»]
3PKJX-ray2.12A/B/C/D/E/F2-355[»]
3ZG6X-ray2.20A1-296[»]
ProteinModelPortaliQ8N6T7.
SMRiQ8N6T7.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ8N6T7.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini35 – 274Deacetylase sirtuin-typePROSITE-ProRule annotationAdd BLAST240

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi287 – 345Pro-richAdd BLAST59

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.
HOVERGENiHBG060028.
InParanoidiQ8N6T7.
KOiK11416.
OMAiNVLDWEH.
OrthoDBiEOG091G0FOW.
PhylomeDBiQ8N6T7.
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]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8N6T7-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL VWQSSSVVFH
60 70 80 90 100
TGAGISTASG IPDFRGPHGV WTMEERGLAP KFDTTFESAR PTQTHMALVQ
110 120 130 140 150
LERVGLLRFL VSQNVDGLHV RSGFPRDKLA ELHGNMFVEE CAKCKTQYVR
160 170 180 190 200
DTVVGTMGLK ATGRLCTVAK ARGLRACRGE LRDTILDWED SLPDRDLALA
210 220 230 240 250
DEASRNADLS ITLGTSLQIR PSGNLPLATK RRGGRLVIVN LQPTKHDRHA
260 270 280 290 300
DLRIHGYVDE VMTRLMKHLG LEIPAWDGPR VLERALPPLP RPPTPKLEPK
310 320 330 340 350
EESPTRINGS IPAGPKQEPC AQHNGSEPAS PKRERPTSPA PHRPPKRVKA

KAVPS
Length:355
Mass (Da):39,119
Last modified:October 31, 2003 - v2
Checksum:i0C86AAC497130BBF
GO
Isoform 2 (identifier: Q8N6T7-2) [UniParc]FASTAAdd to basket

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

Note: No experimental confirmation available.
Show »
Length:328
Mass (Da):36,065
Checksum:i503805C898FD7769
GO

Sequence cautioni

The sequence AAC34468 differs from that shown. Reason: Erroneous gene model prediction.Curated
The sequence AAD15478 differs from that shown. Reason: Erroneous gene model prediction.Curated
The sequence AAH04218 differs from that shown. Reason: Erroneous translation. Wrong choice of CCDS.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti42W → R in CAG33481 (Ref. 3) Curated1
Sequence conflicti249H → Y in AAH04218 (PubMed:15489334).Curated1
Sequence conflicti267K → E in AAF43432 (PubMed:10873683).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01715446S → N.3 PublicationsCorresponds to variant rs352493dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_008733179 – 205Missing in isoform 2. 1 PublicationAdd BLAST27

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS12122.1. [Q8N6T7-1]
CCDS54199.1. [Q8N6T7-2]
RefSeqiNP_001180214.1. NM_001193285.2. [Q8N6T7-2]
NP_001307987.1. NM_001321058.1.
NP_001307988.1. NM_001321059.1.
NP_001307989.1. NM_001321060.1.
NP_001307990.1. NM_001321061.1.
NP_001307991.1. NM_001321062.1.
NP_001307992.1. NM_001321063.1.
NP_001307993.1. NM_001321064.1.
NP_057623.2. NM_016539.3. [Q8N6T7-1]
UniGeneiHs.423756.

Genome annotation databases

EnsembliENST00000305232; ENSP00000305310; ENSG00000077463. [Q8N6T7-2]
ENST00000337491; ENSP00000337332; ENSG00000077463. [Q8N6T7-1]
GeneIDi51548.
KEGGihsa:51548.
UCSCiuc002lzo.4. human. [Q8N6T7-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS12122.1. [Q8N6T7-1]
CCDS54199.1. [Q8N6T7-2]
RefSeqiNP_001180214.1. NM_001193285.2. [Q8N6T7-2]
NP_001307987.1. NM_001321058.1.
NP_001307988.1. NM_001321059.1.
NP_001307989.1. NM_001321060.1.
NP_001307990.1. NM_001321061.1.
NP_001307991.1. NM_001321062.1.
NP_001307992.1. NM_001321063.1.
NP_001307993.1. NM_001321064.1.
NP_057623.2. NM_016539.3. [Q8N6T7-1]
UniGeneiHs.423756.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3K35X-ray2.00A/B/C/D/E/F3-318[»]
3PKIX-ray2.04A/B/C/D/E/F2-355[»]
3PKJX-ray2.12A/B/C/D/E/F2-355[»]
3ZG6X-ray2.20A1-296[»]
ProteinModelPortaliQ8N6T7.
SMRiQ8N6T7.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119603. 176 interactors.
DIPiDIP-47346N.
IntActiQ8N6T7. 17 interactors.
MINTiMINT-1374731.
STRINGi9606.ENSP00000337332.

Chemistry databases

BindingDBiQ8N6T7.
ChEMBLiCHEMBL2163182.
GuidetoPHARMACOLOGYi2712.

PTM databases

iPTMnetiQ8N6T7.
PhosphoSitePlusiQ8N6T7.

Polymorphism and mutation databases

BioMutaiSIRT6.
DMDMi38258612.

Proteomic databases

EPDiQ8N6T7.
MaxQBiQ8N6T7.
PaxDbiQ8N6T7.
PeptideAtlasiQ8N6T7.
PRIDEiQ8N6T7.

Protocols and materials databases

DNASUi51548.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000305232; ENSP00000305310; ENSG00000077463. [Q8N6T7-2]
ENST00000337491; ENSP00000337332; ENSG00000077463. [Q8N6T7-1]
GeneIDi51548.
KEGGihsa:51548.
UCSCiuc002lzo.4. human. [Q8N6T7-1]

Organism-specific databases

CTDi51548.
DisGeNETi51548.
GeneCardsiSIRT6.
H-InvDBHIX0014654.
HGNCiHGNC:14934. SIRT6.
HPAiHPA071776.
MIMi606211. gene.
neXtProtiNX_Q8N6T7.
OpenTargetsiENSG00000077463.
PharmGKBiPA37939.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1905. Eukaryota.
COG0846. LUCA.
GeneTreeiENSGT00530000063706.
HOVERGENiHBG060028.
InParanoidiQ8N6T7.
KOiK11416.
OMAiNVLDWEH.
OrthoDBiEOG091G0FOW.
PhylomeDBiQ8N6T7.
TreeFamiTF106184.

Enzyme and pathway databases

BioCyciZFISH:HS01247-MONOMER.
ReactomeiR-HSA-5693607. Processing of DNA double-strand break ends.
SIGNORiQ8N6T7.

Miscellaneous databases

ChiTaRSiSIRT6. human.
EvolutionaryTraceiQ8N6T7.
GeneWikiiSIRT6.
GenomeRNAii51548.
PROiQ8N6T7.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000077463.
ExpressionAtlasiQ8N6T7. baseline and differential.
GenevisibleiQ8N6T7. HS.

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...

Entry informationi

Entry nameiSIR6_HUMAN
AccessioniPrimary (citable) accession number: Q8N6T7
Secondary accession number(s): B2RCD0
, O75291, Q6IAF5, Q6PK99, Q8NCD2, Q9BSI5, Q9BWP3, Q9NRC7, Q9UQD1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 31, 2003
Last modified: November 2, 2016
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (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.

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.By similarity

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. 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.