UniProt Accession

 SIR1_HUMAN; Q96EB6; Q2XNF6; Q5JVQ0; Q9GZR9; Q9Y6F0 

Genbank Protein ID

 AF083106; AF235040; DQ278604; AL133551; BC012499 

Genbank Nucleotide ID

 AAD40849.2; AAG38486.1; ABB72675.1; CAI16036.1; AAH12499.1 

Protein Name

 NAD-dependent protein deacetylase sirtuin-1 

Protein Synonyms/Alias

 hSIRT1; Regulatory protein SIR2 homolog 1; SIR2-like protein 1; hSIR2; SirtT1 75 kDa fragment; 75SirT1 

Gene Name

 SIRT1 

Gene Synonyms/Alias

 SIR2L1 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
238	PPKRKKRKDINTIED	ubiquitination	[1, 2, 3, 4, 5]
311	KDPRPFFKFAKEIYP	ubiquitination	[1, 4]
314	RPFFKFAKEIYPGQF	ubiquitination	[3]
335	KFIALSDKEGKLLRN	ubiquitination	[3]
338	ALSDKEGKLLRNYTQ	ubiquitination	[3]
499	RLGGEYAKLCCNPVK	ubiquitination	[3]
513	KLSEITEKPPRTQKE	ubiquitination	[3]
601	QMENPDLKNVGSSTG	ubiquitination	[1, 2, 4]
610	VGSSTGEKNERTSVA	ubiquitination	[1, 2, 4]
734	INEAISVKQEVTDMN	sumoylation	[6]

Reference

 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [4] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [5] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [6] SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress.
 Yang Y, Fu W, Chen J, Olashaw N, Zhang X, Nicosia SV, Bhalla K, Bai W.
 Nat Cell Biol. 2007 Nov;9(11):1253-62. [PMID: 17934453] 

Functional Description

 NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A- mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insuline-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double- strand breaks by homologous recombination and specifically single- strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys- 542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1-dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys- 70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transacivation and contributes to its stability. Deacteylates MECOM/EVI1. Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF-kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T-cell hyperactivation during infection. Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization. 

Sequence Annotation

 DOMAIN 244 498 Deacetylase sirtuin-type.
 NP_BIND 261 280 NAD (By similarity).
 NP_BIND 345 348 NAD (By similarity).
 NP_BIND 440 442 NAD (By similarity).
 NP_BIND 465 467 NAD (By similarity).
 REGION 2 268 Interaction with HIST1H1E.
 REGION 143 541 Interaction with KIAA1967/DBC1.
 REGION 538 540 Phosphorylated at one of three serine
 MOTIF 32 39 Nuclear localization signal (By
 MOTIF 138 145 Nuclear export signal (By similarity).
 MOTIF 223 230 Nuclear localization signal (By
 MOTIF 425 431 Nuclear export signal (By similarity).
 ACT_SITE 363 363 Proton acceptor.
 METAL 371 371 Zinc (By similarity).
 METAL 374 374 Zinc (By similarity).
 METAL 395 395 Zinc (By similarity).
 METAL 398 398 Zinc (By similarity).
 BINDING 482 482 NAD; via amide nitrogen (By similarity).
 MOD_RES 2 2 N-acetylalanine.
 MOD_RES 14 14 Phosphoserine.
 MOD_RES 26 26 Phosphoserine.
 MOD_RES 27 27 Phosphoserine; by MAPK8.
 MOD_RES 47 47 Phosphoserine; by MAPK8.
 MOD_RES 159 159 Phosphoserine (Probable).
 MOD_RES 162 162 Phosphoserine (Probable).
 MOD_RES 172 172 Phosphoserine.
 MOD_RES 173 173 Phosphoserine.
 MOD_RES 395 395 S-nitrosocysteine (By similarity).
 MOD_RES 398 398 S-nitrosocysteine (By similarity).
 MOD_RES 530 530 Phosphothreonine; by DYRK1A, DYRK3 and
 MOD_RES 535 535 Phosphoserine.
 MOD_RES 544 544 Phosphothreonine (Probable).
 MOD_RES 545 545 Phosphoserine (Probable).
 MOD_RES 659 659 Phosphoserine; by CaMK2 (By similarity).
 MOD_RES 661 661 Phosphoserine; by CaMK2 (Probable).
 MOD_RES 719 719 Phosphothreonine.
 MOD_RES 747 747 Phosphoserine.  

Keyword

 3D-structure; Acetylation; Alternative splicing; Apoptosis; Complete proteome; Cytoplasm; Developmental protein; Differentiation; Host-virus interaction; Hydrolase; Metal-binding; Methylation; Mitochondrion; Myogenesis; NAD; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; rRNA processing; S-nitrosylation; Transcription; Transcription regulation; Zinc. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 747 AA 

Protein Sequence

Gene Ontology

 GO:0005677; C:chromatin silencing complex; IDA:UniProtKB.
 GO:0005737; C:cytoplasm; IDA:BHF-UCL.
 GO:0005719; C:nuclear euchromatin; IDA:UniProtKB.
 GO:0005720; C:nuclear heterochromatin; IDA:UniProtKB.
 GO:0005637; C:nuclear inner membrane; IDA:UniProtKB.
 GO:0005730; C:nucleolus; IDA:BHF-UCL.
 GO:0016605; C:PML body; IDA:BHF-UCL.
 GO:0033553; C:rDNA heterochromatin; IDA:UniProtKB.
 GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO:0070403; F:NAD+ binding; IEA:InterPro.
 GO:0046969; F:NAD-dependent histone deacetylase activity (H3-K9 specific); ISS:UniProtKB.
 GO:0003714; F:transcription corepressor activity; IDA:BHF-UCL.
 GO:0001525; P:angiogenesis; IDA:UniProtKB.
 GO:0007569; P:cell aging; TAS:BHF-UCL.
 GO:0001678; P:cellular glucose homeostasis; ISS:UniProtKB.
 GO:0070301; P:cellular response to hydrogen peroxide; IDA:BHF-UCL.
 GO:0071456; P:cellular response to hypoxia; IMP:UniProtKB.
 GO:0071479; P:cellular response to ionizing radiation; ISS:UniProtKB.
 GO:0009267; P:cellular response to starvation; ISS:BHF-UCL.
 GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
 GO:0035356; P:cellular triglyceride homeostasis; ISS:UniProtKB.
 GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
 GO:0000183; P:chromatin silencing at rDNA; IDA:UniProtKB.
 GO:0006260; P:DNA replication; TAS:BHF-UCL.
 GO:0000731; P:DNA synthesis involved in DNA repair; ISS:UniProtKB.
 GO:0006343; P:establishment of chromatin silencing; IDA:BHF-UCL.
 GO:0055089; P:fatty acid homeostasis; ISS:UniProtKB.
 GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IMP:UniProtKB.
 GO:0006344; P:maintenance of chromatin silencing; IMP:BHF-UCL.
 GO:0006346; P:methylation-dependent chromatin silencing; TAS:UniProtKB.
 GO:0007517; P:muscle organ development; IEA:UniProtKB-KW.
 GO:0060766; P:negative regulation of androgen receptor signaling pathway; IMP:BHF-UCL.
 GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
 GO:2000480; P:negative regulation of cAMP-dependent protein kinase activity; IDA:UniProtKB.
 GO:0030308; P:negative regulation of cell growth; IMP:BHF-UCL.
 GO:2000655; P:negative regulation of cellular response to testosterone stimulus; IMP:BHF-UCL.
 GO:2000773; P:negative regulation of cellular senescence; IDA:UniProtKB.
 GO:0043518; P:negative regulation of DNA damage response, signal transduction by p53 class mediator; IDA:BHF-UCL.
 GO:0045599; P:negative regulation of fat cell differentiation; ISS:BHF-UCL.
 GO:0051097; P:negative regulation of helicase activity; IDA:UniProtKB.
 GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IDA:UniProtKB.
 GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; ISS:BHF-UCL.
 GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
 GO:2000757; P:negative regulation of peptidyl-lysine acetylation; IDA:UniProtKB.
 GO:0031393; P:negative regulation of prostaglandin biosynthetic process; ISS:UniProtKB.
 GO:0051898; P:negative regulation of protein kinase B signaling cascade; IMP:UniProtKB.
 GO:0032007; P:negative regulation of TOR signaling cascade; IMP:UniProtKB.
 GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
 GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISS:UniProtKB.
 GO:0001542; P:ovulation from ovarian follicle; IEA:Compara.
 GO:0018394; P:peptidyl-lysine acetylation; IMP:UniProtKB.
 GO:0034983; P:peptidyl-lysine deacetylation; IDA:BHF-UCL.
 GO:0002821; P:positive regulation of adaptive immune response; IDA:UniProtKB.
 GO:2000481; P:positive regulation of cAMP-dependent protein kinase activity; IMP:UniProtKB.
 GO:0008284; P:positive regulation of cell proliferation; IMP:UniProtKB.
 GO:2000774; P:positive regulation of cellular senescence; IDA:UniProtKB.
 GO:0010875; P:positive regulation of cholesterol efflux; ISS:UniProtKB.
 GO:0031937; P:positive regulation of chromatin silencing; IMP:BHF-UCL.
 GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
 GO:0045739; P:positive regulation of DNA repair; IMP:UniProtKB.
 GO:0046628; P:positive regulation of insulin receptor signaling pathway; IDA:UniProtKB.
 GO:0016239; P:positive regulation of macroautophagy; IDA:UniProtKB.
 GO:2000111; P:positive regulation of macrophage apoptotic process; ISS:UniProtKB.
 GO:0045348; P:positive regulation of MHC class II biosynthetic process; IDA:UniProtKB.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
 GO:0043161; P:proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
 GO:0031648; P:protein destabilization; ISS:UniProtKB.
 GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
 GO:0000720; P:pyrimidine dimer repair by nucleotide-excision repair; IMP:UniProtKB.
 GO:0070857; P:regulation of bile acid biosynthetic process; ISS:UniProtKB.
 GO:0032071; P:regulation of endodeoxyribonuclease activity; IMP:UniProtKB.
 GO:0010906; P:regulation of glucose metabolic process; ISS:UniProtKB.
 GO:0007346; P:regulation of mitotic cell cycle; IDA:UniProtKB.
 GO:0035358; P:regulation of peroxisome proliferator activated receptor signaling pathway; ISS:BHF-UCL.
 GO:0033158; P:regulation of protein import into nucleus, translocation; IMP:UniProtKB.
 GO:0034391; P:regulation of smooth muscle cell apoptotic process; ISS:UniProtKB.
 GO:0032868; P:response to insulin stimulus; ISS:UniProtKB.
 GO:0006364; P:rRNA processing; IEA:UniProtKB-KW.
 GO:0000012; P:single strand break repair; IMP:UniProtKB.
 GO:0007283; P:spermatogenesis; IEA:Compara.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0006642; P:triglyceride mobilization; ISS:BHF-UCL.
 GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW.
 GO:0050872; P:white fat cell differentiation; ISS:BHF-UCL. 

Interpro

 IPR003000; Sirtuin.
 IPR026591; Sirtuin_cat_small_dom.
 IPR026590; Ssirtuin_cat_dom. 

Pfam

 PF02146; SIR2 

SMART

  

PROSITE

 PS50305; SIRTUIN 

PRINTS