Reviewed, UniProtKB/Swiss-Prot Q96EB6 (SIRT1_HUMAN)

Names and origin

Protein names

Recommended name:
    NAD-dependent deacetylase sirtuin-1
      Short name=hSIRT1
    EC=3.5.1.-
Alternative name(s):
    SIR2-like protein 1
      Short name=hSIR2

Gene names

Name:	SIRT1
Synonyms:	SIR2L1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	747 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	NAD-dependent deacetylase, which regulates processes such as apoptosis and muscle differentiation by deacetylating key proteins. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Involved in HES1- and HEY2-mediated transcriptional repression. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. May serve as a sensor of the cytosolic ratio of NAD+/NADH, which is essential in skeletal muscle cell differentiation. Despite some ability to deacetylate histones in vitro, such activity is either weak or inexistent in vivo. In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. Ref.6 Ref.7
Catalytic activity	NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein. Ref.7
Cofactor	Binds 1 zinc ion per subunit By similarity.
Enzyme regulation	Inhibited by nicotinamide. Activated by resveratrol (3,5,4'-trihydroxy-trans-stilbene), butein (3,4,2',4'-tetrahydroxychalcone), piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene), Isoliquiritigenin (4,2',4'-trihydroxychalcone), fisetin (3,7,3',4'-tetrahydroxyflavone) and quercetin (3,5,7,3',4'-pentahydroxyflavone). RPS19BP1/AROS acts as a positive regulator of deacetylation activity. Ref.8 Ref.9
Subunit structure	Interacts with TAF1B. Found in a complex with PCAF and MYOD1 By similarity. Interacts with MLLT7/FOXO4, HES1, HEY2, p53/TP53 and PML. Interacts with RPS19BP1/AROS.
Subcellular location	Nucleus. Note: Recruited to the nuclear bodies via its interaction with PML. Ref.6 Ref.7
Tissue specificity	Widely expressed. Ref.1
Miscellaneous	Red wine, which contains resveratrol, may participate in activation of sirtuin proteins, and may therefore participate in an extended lifespan as it has been observed in yeast.
Sequence similarities	Belongs to the sirtuin family. Contains 1 deacetylase sirtuin-type domain.

Ontologies

Keywords
Biological process	Apoptosis Differentiation Host-virus interaction Myogenesis Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Ligand	Metal-binding NAD Zinc
Molecular function	Developmental protein Hydrolase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	DNA repair Traceable author statement. Source: UniProtKB DNA replication Traceable author statement. Source: UniProtKB apoptosis Inferred from electronic annotation. Source: UniProtKB-KW cell aging Ref.6 Traceable author statement. Source: UniProtKB cellular response to starvation Inferred from sequence or structural similarity. Source: UniProtKB establishment of chromatin silencing Inferred from direct assay. Source: UniProtKB histone deacetylation Ref.7 Inferred from direct assay. Source: UniProtKB interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW maintenance of chromatin silencing Inferred from mutant phenotype. Source: UniProtKB muscle organ development Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of DNA damage response, signal transduction by p53 class mediator Ref.6 Inferred from direct assay. Source: UniProtKB negative regulation of fat cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of helicase activity Inferred from direct assay. Source: UniProtKB negative regulation of transcription factor activity Ref.6 Inferred from direct assay. Source: UniProtKB peptidyl-lysine deacetylation Inferred from direct assay. Source: UniProtKB positive regulation of anti-apoptosis Traceable author statement. Source: UniProtKB positive regulation of chromatin silencing Inferred from mutant phenotype. Source: UniProtKB regulation of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell proliferation Ref.7 Inferred from mutant phenotype. Source: UniProtKB regulation of protein import into nucleus, translocation Inferred from mutant phenotype. Source: UniProtKB regulation of transcription from RNA polymerase II promoter by nuclear hormone receptor Inferred from sequence or structural similarity. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW triglyceride mobilization Inferred from sequence or structural similarity. Source: UniProtKB white fat cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	PML body Ref.7 Inferred from direct assay. Source: UniProtKB cytoplasm Inferred from direct assay. Source: HPA nuclear envelope Inferred from direct assay. Source: UniProtKB nucleolus Inferred from direct assay. Source: UniProtKB
Molecular function	NAD binding Inferred from electronic annotation. Source: InterPro NAD-dependent histone deacetylase activity Ref.7 Inferred from direct assay. Source: UniProtKB histone binding Inferred from physical interaction. Source: UniProtKB identical protein binding Inferred from physical interaction. Source: UniProtKB p53 binding Ref.6 Inferred from physical interaction. Source: UniProtKB protein C-terminus binding Inferred from physical interaction. Source: UniProtKB protein domain specific binding Inferred from sequence or structural similarity. Source: UniProtKB transcription corepressor activity Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Arntl	Q9WTL8-2	1	EBI-1802965,EBI-644559	From a different organism.
KIAA0409	O43159	1	EBI-1802965,EBI-2008793
Per2	O54943	1	EBI-1802965,EBI-1266779	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 747	747	NAD-dependent deacetylase sirtuin-1		PRO_0000110256
Regions
	Domain	244 – 498	255	Deacetylase sirtuin-type
	Nucleotide binding	261 – 280	20	NAD By similarity
	Nucleotide binding	345 – 349	5	NAD By similarity
	Compositional bias	54 – 98	45	Ala-rich
	Compositional bias	122 – 127	6	Poly-Asp
	Compositional bias	128 – 134	7	Poly-Glu
Sites
	Active site	363	1	Proton acceptor
	Metal binding	371	1	Zinc By similarity
	Metal binding	374	1	Zinc By similarity
	Metal binding	395	1	Zinc By similarity
	Metal binding	398	1	Zinc By similarity
Amino acid modifications
	Modified residue	27	1	Phosphoserine Ref.11
	Modified residue	47	1	Phosphoserine Ref.11 Ref.13 Ref.14 Ref.17 Ref.18 Ref.19
	Modified residue	719	1	Phosphothreonine Ref.19
Natural variations
	Natural variant	3	1	D → E Ref.3		VAR_025148
	Natural variant	484	1	V → D: dbSNP rs1063111.		VAR_051976
Experimental info
	Mutagenesis	363	1	H → Y: Loss of function. Ref.6 Ref.7 Ref.2
	Sequence conflict	386 – 389	4	DIFN → ALFS in AAH12499. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Q96EB6-1 [UniParc]. Last modified October 31, 2003. Version 2. Checksum: 2D3BEA6D73DA229F	FASTA	747	81,681
	10 20 30 40 50 60 MADEAALALQ PGGSPSAAGA DREAASSPAG EPLRKRPRRD GPGLERSPGE PGGAAPEREV 70 80 90 100 110 120 PAAARGCPGA AAAALWREAE AEAAAAGGEQ EAQATAAAGE GDNGPGLQGP SREPPLADNL 130 140 150 160 170 180 YDEDDDDEGE EEEEAAAAAI GYRDNLLFGD EIITNGFHSC ESDEEDRASH ASSSDWTPRP 190 200 210 220 230 240 RIGPYTFVQQ HLMIGTDPRT ILKDLLPETI PPPELDDMTL WQIVINILSE PPKRKKRKDI 250 260 270 280 290 300 NTIEDAVKLL QECKKIIVLT GAGVSVSCGI PDFRSRDGIY ARLAVDFPDL PDPQAMFDIE 310 320 330 340 350 360 YFRKDPRPFF KFAKEIYPGQ FQPSLCHKFI ALSDKEGKLL RNYTQNIDTL EQVAGIQRII 370 380 390 400 410 420 QCHGSFATAS CLICKYKVDC EAVRGDIFNQ VVPRCPRCPA DEPLAIMKPE IVFFGENLPE 430 440 450 460 470 480 QFHRAMKYDK DEVDLLIVIG SSLKVRPVAL IPSSIPHEVP QILINREPLP HLHFDVELLG 490 500 510 520 530 540 DCDVIINELC HRLGGEYAKL CCNPVKLSEI TEKPPRTQKE LAYLSELPPT PLHVSEDSSS 550 560 570 580 590 600 PERTSPPDSS VIVTLLDQAA KSNDDLDVSE SKGCMEEKPQ EVQTSRNVES IAEQMENPDL 610 620 630 640 650 660 KNVGSSTGEK NERTSVAGTV RKCWPNRVAK EQISRRLDGN QYLFLPPNRY IFHGAEVYSD 670 680 690 700 710 720 SEDDVLSSSS CGSNSDSGTC QSPSLEEPME DESEIEEFYN GLEDEPDVPE RAGGAGFGTD 730 740 GDDQEAINEA ISVKQEVTDM NYPSNKS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity." Frye R.A. Biochem. Biophys. Res. Commun. 260:273-279(1999) [PubMed: 10381378] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Tissue: Testis.
[2]	"Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression." Takata T., Ishikawa F. Biochem. Biophys. Res. Commun. 301:250-257(2003) [PubMed: 12535671] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH HES1 AND HEY2, MUTAGENESIS OF HIS-363.
[3]	NIEHS SNPs program Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLU-3.
[4]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] OF 124-747. Tissue: Prostate.
[6]	"hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase." Vaziri H., Dessain S.K., Ng Eaton E., Imai S., Frye R.A., Pandita T.K., Guarente L., Weinberg R.A. Cell 107:149-159(2001) [PubMed: 11672523] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH TP53, MUTAGENESIS OF HIS-363.
[7]	"Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence." Langley E., Pearson M., Faretta M., Bauer U.-M., Frye R.A., Minucci S., Pelicci P.G., Kouzarides T. EMBO J. 21:2383-2396(2002) [PubMed: 12006491] [Abstract] Cited for: FUNCTION, ENZYME ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH PML, MUTAGENESIS OF HIS-363.
[8]	"Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1." Bitterman K.J., Anderson R.M., Cohen H.Y., Latorre-Esteves M., Sinclair D.A. J. Biol. Chem. 277:45099-45107(2002) [PubMed: 12297502] [Abstract] Cited for: ENZYME REGULATION.
[9]	"Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan." Howitz K.T., Bitterman K.J., Cohen H.Y., Lamming D.W., Lavu S., Wood J.G., Zipkin R.E., Chung P., Kisielewski A., Zhang L.-L., Scherer B., Sinclair D.A. Nature 425:191-196(2003) [PubMed: 12939617] [Abstract] Cited for: ENZYME REGULATION.
[10]	"FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1)." van der Horst A., Tertoolen L.G.J., de Vries-Smits L.M.M., Frye R.A., Medema R.H., Burgering B.M.T. J. Biol. Chem. 279:28873-28879(2004) [PubMed: 15126506] [Abstract] Cited for: INTERACTION WITH MLLT7.
[11]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-27 AND SER-47, MASS SPECTROMETRY. Tissue: Epithelium.
[12]	"SIRT1 regulates HIV transcription via Tat deacetylation." Pagans S., Pedal A., North B.J., Kaehlcke K., Marshall B.L., Dorr A., Hetzer-Egger C., Henklein P., Frye R., McBurney M.W., Hruby H., Jung M., Verdin E., Ott M. PLoS Biol. 3:210-220(2005) [PubMed: 15719057] [Abstract] Cited for: INTERACTION WITH HIV-1 TAT.
[13]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47, MASS SPECTROMETRY. Tissue: Epithelium.
[14]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47, MASS SPECTROMETRY. Tissue: Epithelium.
[15]	"Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity." Kim E.-J., Kho J.-H., Kang M.-R., Um S.-J. Mol. Cell 28:277-290(2007) [PubMed: 17964266] [Abstract] Cited for: INTERACTION WITH RPS19BP1.
[16]	Erratum Kim E.-J., Kho J.-H., Kang M.-R., Um S.-J. Mol. Cell 28:513-513(2007)
[17]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47, MASS SPECTROMETRY. Tissue: Epithelium.
[18]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47, MASS SPECTROMETRY.
[19]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47 AND THR-719, MASS SPECTROMETRY.
[20]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF083106 mRNA. Translation: AAD40849.2. AF235040 mRNA. Translation: AAG38486.1. DQ278604 Genomic DNA. Translation: ABB72675.1. AL133551 Genomic DNA. Translation: CAI16036.1. BC012499 mRNA. Translation: AAH12499.1. Different initiation.
IPI	IPI00016802.
RefSeq	NP_036370.2.
UniGene	Hs.369779
3D structure databases
HSSP	HSSP built from PDB template 1J8F based on UniProtKB Q8IXJ6.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q96EB6. 4 interactions.
PTM databases
PhosphoSite	Q96EB6.
Proteomic databases
PeptideAtlas	Q96EB6.
PRIDE	Q96EB6.
Genome annotation databases
Ensembl	ENSG00000096717. Homo sapiens. [Contig view]
GeneID	23411.
KEGG	hsa:23411.
NMPDR	fig|9606.3.peg.4026.
Organism-specific databases
GeneCards	GC10P069314.
H-InvDB	HIX0008867.
HGNC	HGNC:14929. SIRT1.
HPA	CAB003855. HPA006295.
MIM	604479. gene.
PharmGKB	PA37935.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q96EB6.
HOVERGEN	Q96EB6.
OMA	Q96EB6. AGEPLRK.
Enzyme and pathway databases
Pathway_Interaction_DB	foxopathway. FoxO family signaling. ar_tf_pathway. Regulation of Androgen receptor activity. hdac_classi_pathway. Signaling events mediated by HDAC Class I. hdac_classiii_pathway. Signaling events mediated by HDAC Class III.
Gene expression databases
ArrayExpress	Q96EB6.
Bgee	Q96EB6.
CleanEx	HS_SIRT1.
GermOnline	ENSG00000096717. Homo sapiens.
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	45603.
SOURCE	Search...

Entry information

Entry name

SIRT1_HUMAN

Accession

Primary (citable) accession number: Q96EB6
Secondary accession number(s): Q2XNF6 , Q5JVQ0, Q9GZR9, Q9Y6F0

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 31, 2003
Last sequence update:	October 31, 2003
Last modified:	June 16, 2009
This is version 78 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)