Reviewed, UniProtKB/Swiss-Prot P59941 (SIRT6_MOUSE)

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

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	334 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. Ref.3 Ref.4 Ref.5 Ref.6
Catalytic activity	NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein. Ref.2
Cofactor	Binds 1 zinc ion per subunit By similarity.
Subcellular location	Nucleus. Note: Predominantly nuclear. Associated with chromatin. Ref.3 Ref.2
Tissue specificity	Highest levels are found in muscle, thymus, spleen, brain and heart (at protein level). Ref.3 Ref.2
Developmental stage	Expression peaks at embryonic day 11 and persists into adulthood. Ref.2
Disruption phenotype	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. Ref.3
Sequence similarities	Belongs to the sirtuin family. Contains 1 deacetylase sirtuin-type domain.
Caution	Was originally (Ref.2) thought to be a protein ADP-ribosyltransferase.

Ontologies

Keywords
Cellular component	Nucleus
Ligand	Metal-binding NAD Zinc
Molecular function	Hydrolase
Gene Ontology (GO)
Biological process	chromatin silencing Inferred from electronic annotation. Source: InterPro protein amino acid ADP-ribosylation Ref.2 Inferred from direct assay. Source: UniProtKB protein amino acid deacetylation Inferred from electronic annotation. Source: InterPro
Cellular component	nuclear telomeric heterochromatin Inferred from sequence or structural similarity. Source: UniProtKB nucleoplasm Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	NAD binding Inferred from electronic annotation. Source: InterPro NAD(P)+-protein-arginine ADP-ribosyltransferase activity Ref.2 Inferred from direct assay. Source: UniProtKB NAD-dependent histone deacetylase activity (H3-K9 specific) Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 334	334	NAD-dependent deacetylase sirtuin-6		PRO_0000110270
Regions
	Domain	35 – 274	240	Deacetylase sirtuin-type
	Nucleotide binding	52 – 71	20	NAD By similarity
	Nucleotide binding	113 – 117	5	NAD By similarity
Sites
	Active site	133	1	Proton acceptor By similarity
	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
Experimental info
	Mutagenesis	56	1	S → A: Loss of activity. Ref.2
	Mutagenesis	133	1	H → Y: Loss of activity. Ref.5 Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P59941-1 [UniParc]. Last modified October 31, 2003. Version 1. Checksum: 75FD950B42D68A1A	FASTA	334	36,920
	10 20 30 40 50 60 MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL MWQSSSVVFH TGAGISTASG 70 80 90 100 110 120 IPDFRGPHGV WTMEERGLAP KFDTTFENAR PSKTHMALVQ LERMGFLSFL VSQNVDGLHV 130 140 150 160 170 180 RSGFPRDKLA ELHGNMFVEE CPKCKTQYVR DTVVGTMGLK ATGRLCTVAK TRGLRACRGE 190 200 210 220 230 240 LRDTILDWED SLPDRDLMLA DEASRTADLS VTLGTSLQIR PSGNLPLATK RRGGRLVIVN 250 260 270 280 290 300 LQPTKHDRQA DLRIHGYVDE VMCRLMKHLG LEIPAWDGPC VLDKALPPLP RPVALKAEPP 310 320 330 VHLNGAVHVS YKSKPNSPIL HRPPKRVKTE AAPS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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: 15489334] [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: 15795229] [Abstract] Cited for: CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, MUTAGENESIS OF SER-56 AND HIS-133.
[3]	"Genomic instability and aging-like phenotype in the absence of mammalian SIRT6." Mostoslavsky R., Chua K.F., Lombard D.B., Pang W.W., Fischer M.R., Gellon L., Liu P., Mostoslavsky G., Franco S., Murphy M.M., Mills K.D., Patel P., Hsu J.T., Hong A.L., Ford E., Cheng H.-L., Kennedy C., Nunez N. , Bronson R., Frendewey D., Auerbach W., Valenzuela D., Karow M., Hottiger M.O., Hursting S., Barrett J.C., Guarente L., Mulligan R., Demple B., Yancopoulos G.D., Alt F.W. Cell 124:315-329(2006) [PubMed: 16439206] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[4]	"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.
[5]	"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: 19597350] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF HIS-133.
[6]	"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: 19151729] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	BC052763 mRNA. Translation: AAH52763.1.
IPI	IPI00113449.
RefSeq	NP_853617.1.
UniGene	Mm.131825 Mm.25643
3D structure databases
ModBase	Search...
Protein-protein interaction databases
STRING	P59941.
PTM databases
PhosphoSite	P59941.
Proteomic databases
PRIDE	P59941.
Genome annotation databases
Ensembl	ENSMUST00000042923; ENSMUSP00000048971; ENSMUSG00000034748; Mus musculus. [Genome view]
GeneID	50721.
KEGG	mmu:50721.
UCSC	uc007giy.1. mouse.
Organism-specific databases
CTD	50721.
MGI	MGI:1354161. Sirt6.
Phylogenomic databases
HOGENOM	P59941.
HOVERGEN	P59941.
OMA	IPAWDGP.
Enzyme and pathway databases
BRENDA	2.4.2.31. 244.
Gene expression databases
ArrayExpress	P59941.
Bgee	P59941.
Genevestigator	P59941.
GermOnline	ENSMUSG00000034748. Mus musculus.
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	307573.
SOURCE	Search...

Entry information

Entry name

SIRT6_MOUSE

Accession

Primary (citable) accession number: P59941

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 31, 2003
Last sequence update:	October 31, 2003
Last modified:	November 3, 2009
This is version 58 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)