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Protein

NAD-dependent protein deacetylase sirtuin-1

Gene

SIRT1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 (PubMed:11672523, PubMed:12006491, PubMed:14976264, PubMed:14980222, PubMed:15126506, PubMed:15152190, PubMed:15205477, PubMed:15469825, PubMed:15692560, PubMed:16079181, PubMed:16166628, PubMed:16892051, PubMed:16998810, PubMed:17283066, PubMed:17290224, PubMed:17334224, PubMed:17505061, PubMed:17612497, PubMed:17620057, PubMed:17936707, PubMed:18203716, PubMed:18296641, PubMed:18662546, PubMed:18687677, PubMed:19188449, PubMed:19220062, PubMed:19364925, PubMed:19690166, PubMed:19934257, PubMed:20097625, PubMed:20100829, PubMed:20203304, PubMed:20375098, PubMed:20620956, PubMed:20670893, PubMed:20817729, PubMed:20955178, PubMed:21149730, PubMed:21245319, PubMed:21471201, PubMed:21504832, PubMed:21555002, PubMed:21698133, PubMed:21701047, PubMed:21775285, PubMed:21807113, PubMed:21841822, PubMed:21890893, PubMed:21947282, PubMed:22274616, PubMed:24415752, PubMed:24824780). Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression (PubMed:15469825). Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively (PubMed:15152190, PubMed:14980222, PubMed:14976264). Serves as a sensor of the cytosolic ratio of NAD+/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction (PubMed:15205477). 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) (By similarity). 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 (PubMed:18485871). 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 (PubMed:18485871, PubMed:21504832). Deacetylates 'Lys-266' of SUV39H1, leading to its activation (PubMed:21504832). Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1 (PubMed:19188449). Deacetylates H2A and 'Lys-26' of HIST1H1E (PubMed:15469825). 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 (PubMed:20375098). Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting (By similarity). Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1 (PubMed:15469825, PubMed:18004385). Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2 (PubMed:18004385, PubMed:21504832). 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 (PubMed:18004385, PubMed:21504832). Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence (PubMed:11672523, PubMed:12006491). Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I (By similarity). Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability (PubMed:19364925, PubMed:21807113). 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 (PubMed:14980222, PubMed:14976264, PubMed:21841822). Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis (PubMed:15126506). Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing (PubMed:21947282). Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha (PubMed:15152190). Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1 (PubMed:17620057, PubMed:17283066, PubMed:20100829, PubMed:20620956). Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver (PubMed:15692560). Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation (PubMed:16892051). Involved in HES1- and HEY2-mediated transcriptional repression (PubMed:12535671). In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62' (PubMed:21698133). Deacetylates MEF2D (PubMed:16166628). Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3 (PubMed:17505061). Represses HNF1A-mediated transcription (By similarity). Required for the repression of ESRRG by CREBZF (PubMed:19690166). 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 (PubMed:17936707). Involved in lipid metabolism (PubMed:20817729). Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2 (By similarity). Deacetylates p300/EP300 and PRMT1 (By similarity). Deacetylates ACSS2 leading to its activation, and HMGCS1 deacetylation (PubMed:21701047). 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 insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression (PubMed:17290224, PubMed:20817729). 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 (PubMed:15205477, PubMed:17334224, PubMed:16998810, PubMed:17612497, PubMed:20670893, PubMed:21149730). Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN (PubMed:15205477, PubMed:17334224, PubMed:20097625). 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 (PubMed:18203716). Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1 (PubMed:19934257). 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 (PubMed:18296641). Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation (PubMed:21775285). 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 (PubMed:18687677, PubMed:20203304). 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 transactivation and contributes to its stability (PubMed:21890893). Deacteylates MECOM/EVI1 (PubMed:21555002). Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization (PubMed:22274616). During the neurogenic transition, repress selective NOTCH1-target genes through histone deacetylation in a BCL6-dependent manner and leading to neuronal differentiation. Regulates the circadian expression of several core clock genes, including ARNTL/BMAL1, RORC, PER2 and CRY1 and plays a critical role in maintaining a controlled rhythmicity in histone acetylation, thereby contributing to circadian chromatin remodeling (PubMed:18662546). Deacetylates ARNTL/BMAL1 and histones at the circadian gene promoters in order to facilitate repression by inhibitory components of the circadian oscillator (By similarity). Deacetylates PER2, facilitating its ubiquitination and degradation by the proteosome (By similarity). Protects cardiomyocytes against palmitate-induced apoptosis (By similarity). Deacetylates XBP1 isoform 2; deacetylation decreases protein stability of XBP1 isoform 2 and inhibits its transcriptional activity (PubMed:20955178). Involved in the CCAR2-mediated regulation of PCK1 and NR1D1 (PubMed:24415752). Deacetylates CTNB1 at 'Lys-49' (PubMed:24824780). In POMC (pro-opiomelanocortin) neurons, required for leptin-induced activation of PI3K signaling (By similarity).By similarity54 Publications
Isoform 2: Deacetylates '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.1 Publication
(Microbial infection) 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.1 Publication
SirtT1 75 kDa fragment: Catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly.1 Publication

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.
Calf histone H1 is used as substrate in the in vitro deacetylation assay (PubMed:15469825). As, in vivo, interaction occurs between SIRT1 with HIST1H1E, deacetylation has been validated only for HIST1H1E.1 Publication
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

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

Activity regulationi

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). MAPK8/JNK1 and RPS19BP1/AROS act as positive regulators of deacetylation activity. Negatively regulated by CCAR2.4 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei363Proton acceptor9 Publications1
Metal bindingi371ZincPROSITE-ProRule annotation1
Metal bindingi374ZincPROSITE-ProRule annotation1
Metal bindingi395ZincPROSITE-ProRule annotation1
Metal bindingi398ZincPROSITE-ProRule annotation1
Binding sitei482NAD; via amide nitrogenBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi261 – 280NADBy similarityAdd BLAST20
Nucleotide bindingi345 – 348NADBy similarity4
Nucleotide bindingi440 – 442NADBy similarity3
Nucleotide bindingi465 – 467NADBy similarity3

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, Hydrolase
Biological processApoptosis, Biological rhythms, Differentiation, Host-virus interaction, Myogenesis, rRNA processing, Transcription, Transcription regulation
LigandMetal-binding, NAD, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-3371453 Regulation of HSF1-mediated heat shock response
R-HSA-400253 Circadian Clock
R-HSA-427359 SIRT1 negatively regulates rRNA expression
SABIO-RKiQ96EB6
SignaLinkiQ96EB6
SIGNORiQ96EB6

Names & Taxonomyi

Protein namesi
Recommended name:
NAD-dependent protein deacetylase sirtuin-1 (EC:3.5.1.-)
Short name:
hSIRT1
Alternative name(s):
Regulatory protein SIR2 homolog 1
SIR2-like protein 1
Short name:
hSIR2
Cleaved into the following chain:
SirtT1 75 kDa fragment
Short name:
75SirT1
Gene namesi
Name:SIRT1
Synonyms:SIR2L1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

EuPathDBiHostDB:ENSG00000096717.11
HGNCiHGNC:14929 SIRT1
MIMi604479 gene
neXtProtiNX_Q96EB6

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi27S → A: Greatly diminishes phosphorylation by MAPK8; when associated with A-47 and A-530. 1 Publication1
Mutagenesisi47S → A: Blocks residue phosphorylation, restores deacetylation activity and inhibits DNA damage-induced apoptosis. 2 Publications1
Mutagenesisi47S → A: Greatly diminishes phosphorylation by MAPK8; when associated with A-27 and A-530. 2 Publications1
Mutagenesisi233K → R: Impairs in vitro methylation by SETD7; when associated with R-235, R-236 and R-238. 1 Publication1
Mutagenesisi235K → R: Impairs in vitro methylation by SETD7; when associated with R-233, R-236 and R-238. 1 Publication1
Mutagenesisi236K → R: Impairs in vitro methylation by SETD7; when associated with R-233, R-235 and R-238. 1 Publication1
Mutagenesisi238K → R: Impairs in vitro methylation by SETD7; when associated with R-233, R-235a and R-236. 1 Publication1
Mutagenesisi256 – 257II → KK: Loss of interaction with the sumoylated form of CCAR2. No effect on its deacetylation activity. 1 Publication2
Mutagenesisi363H → Y: Loss of function. Reduces the interaction with CCAR2 and APEX1. Increases acetylation of APEX1. 9 Publications1
Mutagenesisi474F → A: Abolishes phosphorylation at Ser-47, restores deacetylation activity and inhibits DNA damage-induced apoptosis. 1 Publication1
Mutagenesisi530T → A: Greatly diminishes phosphorylation by MAPK8; when associated with A-27 and A-47. 2 Publications1
Mutagenesisi530T → A: Reduces in vitro phosphorylation by CDK1. Impairs cell proliferation and cell cycle progression; when associated with A-540. 2 Publications1
Mutagenesisi540S → A: Reduces in vitro phosphorylation by CDK1. Impairs cell proliferation and cell cycle progression; when associated with A-530. 1 Publication1
Mutagenesisi659S → A: Reduces in vitro phosphorylation by CaMK2; when associated with S-661. Greatly reduces in vivo phosphorylation; when associated with A-661. 1 Publication1
Mutagenesisi661S → A: Reduces in vitro phosphorylation by CaMK2; when associated with S-659. Greatly reduces in vivo phosphorylation; when associated with A-659. 1 Publication1
Mutagenesisi684S → A: No effect on phosphorylation (in vitro and in vivo). 1 Publication1

Organism-specific databases

DisGeNETi23411
OpenTargetsiENSG00000096717
PharmGKBiPA37935

Chemistry databases

ChEMBLiCHEMBL4506
DrugBankiDB05073 SRT501
GuidetoPHARMACOLOGYi2707

Polymorphism and mutation databases

BioMutaiSIRT1
DMDMi38258633

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00001102562 – 747NAD-dependent protein deacetylase sirtuin-1Add BLAST746
ChainiPRO_00004152892 – 533SirtT1 75 kDa fragmentAdd BLAST532

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1
Modified residuei14PhosphoserineCombined sources1 Publication1
Modified residuei26Phosphoserine1 Publication1
Modified residuei27Phosphoserine; by MAPK8Combined sources3 Publications1
Modified residuei47Phosphoserine; by MAPK8Combined sources4 Publications1
Modified residuei159Phosphoserine1 Publication1
Modified residuei162Phosphoserine1 Publication1
Modified residuei172Phosphoserine1 Publication1
Modified residuei173Phosphoserine1 Publication1
Modified residuei395S-nitrosocysteineBy similarity1
Modified residuei398S-nitrosocysteineBy similarity1
Modified residuei530Phosphothreonine; by DYRK1A, DYRK3 and MAPK8Combined sources2 Publications1
Modified residuei535PhosphoserineCombined sources1
Modified residuei544Phosphothreonine1 Publication1
Modified residuei545Phosphoserine1 Publication1
Modified residuei659Phosphoserine; by CaMK2By similarity1
Modified residuei661Phosphoserine; by CaMK21 Publication1
Modified residuei719PhosphothreonineCombined sources1 Publication1
Modified residuei747Phosphoserine1 Publication1

Post-translational modificationi

Methylated on multiple lysine residues; methylation is enhanced after DNA damage and is dispensable for deacetylase activity toward p53/TP53.
Phosphorylated. Phosphorylated by STK4/MST1, resulting in inhibition of SIRT1-mediated p53/TP53 deacetylation. Phosphorylation by MAPK8/JNK1 at Ser-27, Ser-47, and Thr-530 leads to increased nuclear localization and enzymatic activity. Phosphorylation at Thr-530 by DYRK1A and DYRK3 activates deacetylase activity and promotes cell survival. Phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) at Ser-47 inhibits deacetylation activity. Phosphorylated by CaMK2, leading to increased p53/TP53 and NF-kappa-B p65/RELA deacetylation activity (By similarity). Phosphorylation at Ser-27 implicating MAPK9 is linked to protein stability. There is some ambiguity for some phosphosites: Ser-159/Ser-162 and Thr-544/Ser-545.By similarity6 Publications
Proteolytically cleaved by cathepsin B upon TNF-alpha treatment to yield catalytic inactive but stable SirtT1 75 kDa fragment (75SirT1).1 Publication
S-nitrosylated by GAPDH, leading to inhibit the NAD-dependent protein deacetylase activity.By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein, S-nitrosylation

Proteomic databases

EPDiQ96EB6
MaxQBiQ96EB6
PaxDbiQ96EB6
PeptideAtlasiQ96EB6
PRIDEiQ96EB6
ProteomicsDBi76393
76394 [Q96EB6-2]

PTM databases

iPTMnetiQ96EB6
PhosphoSitePlusiQ96EB6

Expressioni

Tissue specificityi

Widely expressed.1 Publication

Inductioni

Up-regulated by methyl methanesulfonate (MMS). In H293T cells by presence of rat calorie restriction (CR) serum.2 Publications

Gene expression databases

BgeeiENSG00000096717 Expressed in 213 organ(s), highest expression level in right adrenal gland
CleanExiHS_SIRT1
ExpressionAtlasiQ96EB6 baseline and differential
GenevisibleiQ96EB6 HS

Organism-specific databases

HPAiCAB003855
HPA006295
HPA052351

Interactioni

Subunit structurei

Interacts with XBP1 isoform 2 (PubMed:20955178). Found in a complex with PCAF and MYOD1. Interacts with FOXO1; the interaction deacetylates FOXO1, resulting in its nuclear retention and promotion of its transcriptional activity Component of the eNoSC complex, composed of SIRT1, SUV39H1 and RRP8. Interacts with HES1, HEY2 and PML. Interacts with RPS19BP1/AROS. Interacts with CCAR2 (via N-terminus); the interaction disrupts the interaction between SIRT1 and p53/TP53. Interacts with SETD7; the interaction induces the dissociation of SIRT1 from p53/TP53 and increases p53/TP53 activity. Interacts with MYCN, NR1I2, CREBZF, TSC2, TLE1, FOS, JUN, NR0B2, PPARG, NCOR, IRS1, IRS2 and NMNAT1. Interacts with HNF1A; the interaction occurs under nutrient restriction. Interacts with SUZ12; the interaction mediates the association with the PRC4 histone methylation complex which is specific as an association with PCR2 and PCR3 complex variants is not found. Interacts with BCL6; leads to a epigenetic repression of specific target genes. Interacts with CLOCK, ARNTL/BMAL1 and PER2 (By similarity). Interacts with PPARA; the interaction seems to be modulated by NAD+ levels (PubMed:24043310). Interacts with NR1H3 and this interaction is inhibited in the presence of CCAR2. Interacts with CHEK2. Interacts with p53/TP53. Exhibits a preferential interaction with sumoylated CCAR2 over its unmodified form.By similarity27 Publications
(Microbial infection) Interacts with HIV-1 Tat.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ACACAQ130853EBI-1802965,EBI-717681
AKT1P317495EBI-1802965,EBI-296087
APEX1P276956EBI-1802965,EBI-1048805
ATG7O953523EBI-1802965,EBI-987834
CCAR2Q8N16316EBI-1802965,EBI-355410
CIITAP330764EBI-1802965,EBI-1538819
CREBZFQ9NS373EBI-1802965,EBI-632965
CSNK2A1P684005EBI-1802965,EBI-347804
CSNK2BP678705EBI-1802965,EBI-348169
DNMT1P2635811EBI-1802965,EBI-719459
DVL1O146402EBI-1802965,EBI-723489
DVL3Q929973EBI-1802965,EBI-739789
E2F1Q010943EBI-1802965,EBI-448924
EP300Q094722EBI-1802965,EBI-447295
FHL2Q141922EBI-1802965,EBI-701903
FOXO1Q127784EBI-1802965,EBI-1108782
Foxo1Q9R1E02EBI-1802965,EBI-1371343From Mus musculus.
FOXO3O435245EBI-1802965,EBI-1644164
FOXO4P981773EBI-1802965,EBI-4481939
HCFC1P516102EBI-1802965,EBI-396176
HES1Q144694EBI-1802965,EBI-2832522
HEY2Q9UBP53EBI-1802965,EBI-750630
IRS2Q9Y4H22EBI-1802965,EBI-1049582
KAT2BQ928313EBI-1802965,EBI-477430
KMT2AQ031645EBI-1802965,EBI-591370
MAP1LC3BQ9GZQ82EBI-1802965,EBI-373144
MECOMQ031122EBI-1802965,EBI-1384862
MTORP423452EBI-1802965,EBI-359260
MYCP011064EBI-1802965,EBI-447544
MYCNP041983EBI-1802965,EBI-878369
NBNO609345EBI-1802965,EBI-494844
Ncor1Q609742EBI-1802965,EBI-349004From Mus musculus.
NHLH2Q025772EBI-1802965,EBI-5378683
NMNAT1Q9HAN93EBI-1802965,EBI-3917542
NR0B2Q154666EBI-1802965,EBI-3910729
Nr1h2Q606442EBI-1802965,EBI-5276809From Mus musculus.
Nr1h3Q9Z0Y92EBI-1802965,EBI-5276764From Mus musculus.
PIK3R1P279863EBI-1802965,EBI-79464
PpargP372383EBI-1802965,EBI-5260705From Mus musculus.
PpargP37238-12EBI-1802965,EBI-6267861From a different organism.
RARAP102763EBI-1802965,EBI-413374
RELAQ042065EBI-1802965,EBI-73886
RPS19BP1Q86WX311EBI-1802965,EBI-4479407
RPTORQ8N1223EBI-1802965,EBI-1567928
RRP8O431593EBI-1802965,EBI-2008793
SETD7Q8WTS611EBI-1802965,EBI-1268586
SNW1Q135737EBI-1802965,EBI-632715
SREBF1P36956-32EBI-1802965,EBI-948338
SUV39H1O434635EBI-1802965,EBI-349968
tatP046083EBI-1802965,EBI-6164389From Human immunodeficiency virus type 1 group M subtype B (isolate HXB2).
TLE1Q047244EBI-1802965,EBI-711424
TP53P0463718EBI-1802965,EBI-366083
TP73O153504EBI-1802965,EBI-389606
TSC2P498152EBI-1802965,EBI-396587
WRNQ141919EBI-1802965,EBI-368417
XPAP230258EBI-1802965,EBI-295222
XRCC6P129567EBI-1802965,EBI-353208

GO - Molecular functioni

Protein-protein interaction databases

BioGridi116983, 262 interactors
ComplexPortaliCPX-467 eNoSc complex
CORUMiQ96EB6
DIPiDIP-29757N
IntActiQ96EB6, 143 interactors
MINTiQ96EB6
STRINGi9606.ENSP00000212015

Chemistry databases

BindingDBiQ96EB6

Structurei

Secondary structure

1747
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ96EB6
SMRiQ96EB6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini244 – 498Deacetylase sirtuin-typePROSITE-ProRule annotationAdd BLAST255

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 268Interaction with HIST1H1E1 PublicationAdd BLAST267
Regioni2 – 139Interaction with CLOCKBy similarityAdd BLAST138
Regioni143 – 541Interaction with CCAR2Add BLAST399
Regioni256 – 259Required for interaction with the sumoylated form of CCAR21 Publication4
Regioni538 – 540Phosphorylated at one of three serine residues3

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi32 – 39Nuclear localization signalBy similarity8
Motifi138 – 145Nuclear export signalBy similarity8
Motifi223 – 230Nuclear localization signalBy similarity8
Motifi425 – 431Nuclear export signalBy similarity7

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi54 – 98Ala-richAdd BLAST45
Compositional biasi122 – 127Poly-Asp6
Compositional biasi128 – 134Poly-Glu7

Sequence similaritiesi

Belongs to the sirtuin family. Class I subfamily.Curated

Phylogenomic databases

eggNOGiKOG2684 Eukaryota
COG0846 LUCA
GeneTreeiENSGT00870000136443
HOGENOMiHOG000038016
HOVERGENiHBG054192
InParanoidiQ96EB6
KOiK11411
OMAiLAIMKPD
OrthoDBiEOG091G07CT
PhylomeDBiQ96EB6
TreeFamiTF105896

Family and domain databases

Gene3Di3.30.1600.10, 1 hit
InterProiView protein in InterPro
IPR029035 DHS-like_NAD/FAD-binding_dom
IPR003000 Sirtuin
IPR026591 Sirtuin_cat_small_dom_sf
IPR026590 Ssirtuin_cat_dom
PfamiView protein in Pfam
PF02146 SIR2, 1 hit
SUPFAMiSSF52467 SSF52467, 1 hit
PROSITEiView protein in PROSITE
PS50305 SIRTUIN, 1 hit

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

This entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: Q96EB6-1) [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
MADEAALALQ PGGSPSAAGA DREAASSPAG EPLRKRPRRD GPGLERSPGE
60 70 80 90 100
PGGAAPEREV PAAARGCPGA AAAALWREAE AEAAAAGGEQ EAQATAAAGE
110 120 130 140 150
GDNGPGLQGP SREPPLADNL YDEDDDDEGE EEEEAAAAAI GYRDNLLFGD
160 170 180 190 200
EIITNGFHSC ESDEEDRASH ASSSDWTPRP RIGPYTFVQQ HLMIGTDPRT
210 220 230 240 250
ILKDLLPETI PPPELDDMTL WQIVINILSE PPKRKKRKDI NTIEDAVKLL
260 270 280 290 300
QECKKIIVLT GAGVSVSCGI PDFRSRDGIY ARLAVDFPDL PDPQAMFDIE
310 320 330 340 350
YFRKDPRPFF KFAKEIYPGQ FQPSLCHKFI ALSDKEGKLL RNYTQNIDTL
360 370 380 390 400
EQVAGIQRII QCHGSFATAS CLICKYKVDC EAVRGDIFNQ VVPRCPRCPA
410 420 430 440 450
DEPLAIMKPE IVFFGENLPE QFHRAMKYDK DEVDLLIVIG SSLKVRPVAL
460 470 480 490 500
IPSSIPHEVP QILINREPLP HLHFDVELLG DCDVIINELC HRLGGEYAKL
510 520 530 540 550
CCNPVKLSEI TEKPPRTQKE LAYLSELPPT PLHVSEDSSS PERTSPPDSS
560 570 580 590 600
VIVTLLDQAA KSNDDLDVSE SKGCMEEKPQ EVQTSRNVES IAEQMENPDL
610 620 630 640 650
KNVGSSTGEK NERTSVAGTV RKCWPNRVAK EQISRRLDGN QYLFLPPNRY
660 670 680 690 700
IFHGAEVYSD SEDDVLSSSS CGSNSDSGTC QSPSLEEPME DESEIEEFYN
710 720 730 740
GLEDEPDVPE RAGGAGFGTD GDDQEAINEA ISVKQEVTDM NYPSNKS
Length:747
Mass (Da):81,681
Last modified:October 31, 2003 - v2
Checksum:i2D3BEA6D73DA229F
GO
Isoform 2 (identifier: Q96EB6-2) [UniParc]FASTAAdd to basket
Also known as: delta-exon8

The sequence of this isoform differs from the canonical sequence as follows:
     454-639: Missing.

Show »
Length:561
Mass (Da):61,066
Checksum:iBFD54C8E408F23BD
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E9PC49E9PC49_HUMAN
NAD-dependent protein deacetylase s...
SIRT1
452Annotation score:
B0QZ35B0QZ35_HUMAN
NAD-dependent protein deacetylase s...
SIRT1
444Annotation score:

Sequence cautioni

The sequence AAH12499 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti386 – 389DIFN → ALFS in AAH12499 (PubMed:15489334).Curated4

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0251483D → E1 PublicationCorresponds to variant dbSNP:rs35671182Ensembl.1
Natural variantiVAR_051976484V → D. Corresponds to variant dbSNP:rs1063111Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_042189454 – 639Missing in isoform 2. CuratedAdd BLAST186

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF083106 mRNA Translation: AAD40849.2
AF235040 mRNA Translation: AAG38486.1
DQ278604 Genomic DNA Translation: ABB72675.1
AL133551 Genomic DNA No translation available.
BC012499 mRNA Translation: AAH12499.1 Different initiation.
CCDSiCCDS7273.1 [Q96EB6-1]
RefSeqiNP_001135970.1, NM_001142498.1
NP_001300978.1, NM_001314049.1
NP_036370.2, NM_012238.4 [Q96EB6-1]
UniGeneiHs.369779

Genome annotation databases

EnsembliENST00000212015; ENSP00000212015; ENSG00000096717 [Q96EB6-1]
GeneIDi23411
KEGGihsa:23411
UCSCiuc001jnd.3 human [Q96EB6-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

NIEHS-SNPs
Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF083106 mRNA Translation: AAD40849.2
AF235040 mRNA Translation: AAG38486.1
DQ278604 Genomic DNA Translation: ABB72675.1
AL133551 Genomic DNA No translation available.
BC012499 mRNA Translation: AAH12499.1 Different initiation.
CCDSiCCDS7273.1 [Q96EB6-1]
RefSeqiNP_001135970.1, NM_001142498.1
NP_001300978.1, NM_001314049.1
NP_036370.2, NM_012238.4 [Q96EB6-1]
UniGeneiHs.369779

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4I5IX-ray2.50A/B241-516[»]
4IF6X-ray2.25A234-510[»]
B641-665[»]
4IG9X-ray2.64A/C/E/G234-510[»]
B/D/F/H641-665[»]
4KXQX-ray1.85A234-510[»]
B641-663[»]
4ZZHX-ray3.10A183-505[»]
4ZZIX-ray2.73A183-505[»]
4ZZJX-ray2.74A183-505[»]
5BTRX-ray3.20A/B/C143-665[»]
ProteinModelPortaliQ96EB6
SMRiQ96EB6
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116983, 262 interactors
ComplexPortaliCPX-467 eNoSc complex
CORUMiQ96EB6
DIPiDIP-29757N
IntActiQ96EB6, 143 interactors
MINTiQ96EB6
STRINGi9606.ENSP00000212015

Chemistry databases

BindingDBiQ96EB6
ChEMBLiCHEMBL4506
DrugBankiDB05073 SRT501
GuidetoPHARMACOLOGYi2707

PTM databases

iPTMnetiQ96EB6
PhosphoSitePlusiQ96EB6

Polymorphism and mutation databases

BioMutaiSIRT1
DMDMi38258633

Proteomic databases

EPDiQ96EB6
MaxQBiQ96EB6
PaxDbiQ96EB6
PeptideAtlasiQ96EB6
PRIDEiQ96EB6
ProteomicsDBi76393
76394 [Q96EB6-2]

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000212015; ENSP00000212015; ENSG00000096717 [Q96EB6-1]
GeneIDi23411
KEGGihsa:23411
UCSCiuc001jnd.3 human [Q96EB6-1]

Organism-specific databases

CTDi23411
DisGeNETi23411
EuPathDBiHostDB:ENSG00000096717.11
GeneCardsiSIRT1
HGNCiHGNC:14929 SIRT1
HPAiCAB003855
HPA006295
HPA052351
MIMi604479 gene
neXtProtiNX_Q96EB6
OpenTargetsiENSG00000096717
PharmGKBiPA37935
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2684 Eukaryota
COG0846 LUCA
GeneTreeiENSGT00870000136443
HOGENOMiHOG000038016
HOVERGENiHBG054192
InParanoidiQ96EB6
KOiK11411
OMAiLAIMKPD
OrthoDBiEOG091G07CT
PhylomeDBiQ96EB6
TreeFamiTF105896

Enzyme and pathway databases

ReactomeiR-HSA-3371453 Regulation of HSF1-mediated heat shock response
R-HSA-400253 Circadian Clock
R-HSA-427359 SIRT1 negatively regulates rRNA expression
SABIO-RKiQ96EB6
SignaLinkiQ96EB6
SIGNORiQ96EB6

Miscellaneous databases

GeneWikiiSirtuin_1
GenomeRNAii23411
PROiPR:Q96EB6
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000096717 Expressed in 213 organ(s), highest expression level in right adrenal gland
CleanExiHS_SIRT1
ExpressionAtlasiQ96EB6 baseline and differential
GenevisibleiQ96EB6 HS

Family and domain databases

Gene3Di3.30.1600.10, 1 hit
InterProiView protein in InterPro
IPR029035 DHS-like_NAD/FAD-binding_dom
IPR003000 Sirtuin
IPR026591 Sirtuin_cat_small_dom_sf
IPR026590 Ssirtuin_cat_dom
PfamiView protein in Pfam
PF02146 SIR2, 1 hit
SUPFAMiSSF52467 SSF52467, 1 hit
PROSITEiView protein in PROSITE
PS50305 SIRTUIN, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSIR1_HUMAN
AccessioniPrimary (citable) accession number: Q96EB6
Secondary accession number(s): Q2XNF6
, Q5JVQ0, Q9GZR9, Q9Y6F0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 31, 2003
Last modified: November 7, 2018
This is version 183 of the entry and version 2 of the sequence. See 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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  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. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
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