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Protein

NAD-dependent protein deacetylase sirtuin-3, mitochondrial

Gene

SIRT3

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

Functioni

NAD-dependent protein deacetylase (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090, PubMed:19535340). Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090). Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5O (PubMed:16788062, PubMed:18680753, PubMed:24121500, PubMed:24252090, PubMed:19535340). Contributes to the regulation of the cellular energy metabolism (PubMed:24252090). Important for regulating tissue-specific ATP levels (PubMed:18794531). In response to metabolic stress, deacetylates transcription factor FOXO3 and recruits FOXO3 and mitochondrial RNA polymerase POLRMT to mtDNA to promote mtDNA transcription (PubMed:23283301).9 Publications

Miscellaneous

Has some ability to deacetylate histones in vitro, but seeing its subcellular location, this is unlikely in vivo.1 Publication

Catalytic activityi

NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein.PROSITE-ProRule annotation1 Publication7 Publications

Cofactori

Zn2+2 PublicationsNote: Binds 1 zinc ion per subunit.2 Publications

Kineticsi

  1. KM=600 µM for NAD1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei248Proton acceptor1
    Metal bindingi256Zinc1
    Metal bindingi259Zinc1
    Metal bindingi280Zinc1
    Metal bindingi283Zinc1
    Binding sitei366NAD; via amide nitrogenBy similarity1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi145 – 165NADAdd BLAST21
    Nucleotide bindingi228 – 231NAD4
    Nucleotide bindingi319 – 321NAD3
    Nucleotide bindingi344 – 346NAD3

    GO - Molecular functioni

    • enzyme binding Source: Ensembl
    • NAD+ ADP-ribosyltransferase activity Source: ProtInc
    • NAD+ binding Source: InterPro
    • NAD-dependent histone deacetylase activity Source: InterPro
    • NAD-dependent protein deacetylase activity Source: Reactome
    • sequence-specific DNA binding Source: UniProtKB
    • zinc ion binding Source: UniProtKB

    GO - Biological processi

    • aerobic respiration Source: UniProtKB
    • aging Source: Ensembl
    • mitochondrion organization Source: Reactome
    • negative regulation of ERK1 and ERK2 cascade Source: Ensembl
    • negative regulation of reactive oxygen species metabolic process Source: Ensembl
    • peptidyl-lysine deacetylation Source: UniProtKB
    • positive regulation of insulin secretion Source: Ensembl
    • protein ADP-ribosylation Source: ProtInc
    • protein deacetylation Source: UniProtKB

    Keywordsi

    Molecular functionHydrolase
    LigandMetal-binding, NAD, Zinc

    Enzyme and pathway databases

    ReactomeiR-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
    SABIO-RKiQ9NTG7
    SIGNORiQ9NTG7

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    NAD-dependent protein deacetylase sirtuin-3, mitochondrial (EC:3.5.1.-7 Publications)
    Short name:
    hSIRT3
    Alternative name(s):
    Regulatory protein SIR2 homolog 3
    SIR2-like protein 3
    Gene namesi
    Name:SIRT3
    Synonyms:SIR2L3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 11

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000142082.14
    HGNCiHGNC:14931 SIRT3
    MIMi604481 gene
    neXtProtiNX_Q9NTG7

    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

    Mitochondrion

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi7R → G or Q: Suppresses targeting to mitochondrion; when associated with G-13 or Q-13. 1 Publication1
    Mutagenesisi13R → G or Q: Suppresses targeting to mitochondrion; when associated with G-7 or Q-7. 1 Publication1
    Mutagenesisi17R → G or Q: Reduces targeting to mitochondrion; when associated with G-21 or Q-21. 1 Publication1
    Mutagenesisi21R → G or Q: Reduces targeting to mitochondrion; when associated with G-17 or Q-17. 1 Publication1
    Mutagenesisi99 – 100RR → GG: Abolishes processing by MPP (in vitro). 1 Publication2
    Mutagenesisi229N → A: Loss of function. 1 Publication1
    Mutagenesisi248H → Y: Loss of function. 3 Publications1

    Organism-specific databases

    DisGeNETi23410
    OpenTargetsiENSG00000142082
    PharmGKBiPA37936

    Chemistry databases

    ChEMBLiCHEMBL4461
    DrugBankiDB02059 Adenosine-5-Diphosphoribose
    GuidetoPHARMACOLOGYi2709

    Polymorphism and mutation databases

    BioMutaiSIRT3
    DMDMi38258651

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_0000032612? – 399NAD-dependent protein deacetylase sirtuin-3, mitochondrial
    Transit peptidei1 – ?MitochondrionSequence analysis

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei122N6-succinyllysineBy similarity1

    Post-translational modificationi

    Processed by mitochondrial processing peptidase (MPP) to give a 28 kDa product. Such processing is probably essential for its enzymatic activity.1 Publication

    Proteomic databases

    EPDiQ9NTG7
    MaxQBiQ9NTG7
    PaxDbiQ9NTG7
    PeptideAtlasiQ9NTG7
    PRIDEiQ9NTG7
    ProteomicsDBi82606
    82607 [Q9NTG7-2]

    PTM databases

    iPTMnetiQ9NTG7
    PhosphoSitePlusiQ9NTG7

    Expressioni

    Tissue specificityi

    Widely expressed.2 Publications

    Gene expression databases

    BgeeiENSG00000142082
    CleanExiHS_SIRT3
    ExpressionAtlasiQ9NTG7 baseline and differential
    GenevisibleiQ9NTG7 HS

    Organism-specific databases

    HPAiCAB037142
    HPA026809

    Interactioni

    Subunit structurei

    Upon metabolic stress, forms a complex composed of FOXO3, SIRT3 and mitochondrial RNA polymerase POLRMT; the complex is recruited to mtDNA in a SIRT3-dependent manner (PubMed:23283301). Also forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT (PubMed:29445193). Interacts with NDUFA9, ACSS1, IDH2 and GDH (PubMed:16788062, PubMed:18794531, PubMed:19535340, PubMed:18680753). Interacts with PCCA (PubMed:23438705).7 Publications

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi116982, 56 interactors
    DIPiDIP-46861N
    IntActiQ9NTG7, 35 interactors
    MINTiQ9NTG7
    STRINGi9606.ENSP00000372191

    Chemistry databases

    BindingDBiQ9NTG7

    Structurei

    Secondary structure

    1399
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi125 – 133Combined sources9
    Turni134 – 136Combined sources3
    Beta strandi140 – 144Combined sources5
    Helixi146 – 152Combined sources7
    Beta strandi157 – 159Combined sources3
    Turni160 – 162Combined sources3
    Helixi164 – 168Combined sources5
    Beta strandi171 – 175Combined sources5
    Helixi176 – 180Combined sources5
    Helixi182 – 187Combined sources6
    Helixi190 – 199Combined sources10
    Beta strandi201 – 203Combined sources3
    Helixi208 – 218Combined sources11
    Beta strandi222 – 227Combined sources6
    Helixi233 – 236Combined sources4
    Helixi241 – 243Combined sources3
    Beta strandi244 – 246Combined sources3
    Beta strandi249 – 256Combined sources8
    Turni257 – 259Combined sources3
    Beta strandi262 – 264Combined sources3
    Helixi265 – 273Combined sources9
    Turni281 – 283Combined sources3
    Beta strandi286 – 291Combined sources6
    Helixi300 – 304Combined sources5
    Helixi305 – 311Combined sources7
    Beta strandi313 – 319Combined sources7
    Helixi327 – 330Combined sources4
    Helixi331 – 333Combined sources3
    Beta strandi340 – 346Combined sources7
    Helixi349 – 353Combined sources5
    Beta strandi359 – 364Combined sources6
    Helixi366 – 377Combined sources12
    Helixi380 – 391Combined sources12

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3GLRX-ray1.80A118-399[»]
    3GLSX-ray2.70A/B/C/D/E/F118-399[»]
    3GLTX-ray2.10A118-399[»]
    3GLUX-ray2.50A118-399[»]
    4BN4X-ray1.30A116-399[»]
    4BN5X-ray3.25A/B/C/D/E/F/G/H/I/J/K/L119-399[»]
    4BV3X-ray2.00A116-399[»]
    4BVBX-ray2.00A116-399[»]
    4BVEX-ray2.05A116-399[»]
    4BVFX-ray2.70A116-399[»]
    4BVGX-ray2.50A116-399[»]
    4BVHX-ray1.90A/B/C116-399[»]
    4C78X-ray2.00A116-399[»]
    4C7BX-ray2.10A117-399[»]
    4FVTX-ray2.47A122-395[»]
    4FZ3X-ray2.10A118-399[»]
    4HD8X-ray2.30A116-399[»]
    4JSRX-ray1.70A118-399[»]
    4JT8X-ray2.26A118-399[»]
    4JT9X-ray2.24A118-399[»]
    4O8ZX-ray2.00A116-399[»]
    4V1CX-ray2.95A/B/E/G/I/K121-394[»]
    5BWNX-ray1.94A118-399[»]
    5BWOX-ray2.38A118-399[»]
    5D7NX-ray1.83A/B/C/D/E/F118-395[»]
    5H4DX-ray3.21A/H121-391[»]
    5YTKX-ray2.70A/B/C/D/E/F121-394[»]
    ProteinModelPortaliQ9NTG7
    SMRiQ9NTG7
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9NTG7

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini126 – 382Deacetylase sirtuin-typePROSITE-ProRule annotationAdd BLAST257

    Sequence similaritiesi

    Belongs to the sirtuin family. Class I subfamily.Curated

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2682 Eukaryota
    COG0846 LUCA
    GeneTreeiENSGT00870000136486
    HOVERGENiHBG057095
    InParanoidiQ9NTG7
    KOiK11413
    OMAiCTGIVKP
    OrthoDBiEOG091G07CT
    PhylomeDBiQ9NTG7
    TreeFamiTF106181

    Family and domain databases

    Gene3Di3.30.1600.10, 2 hits
    InterProiView protein in InterPro
    IPR029035 DHS-like_NAD/FAD-binding_dom
    IPR003000 Sirtuin
    IPR026591 Sirtuin_cat_small_dom_sf
    IPR017328 Sirtuin_class_I
    IPR026590 Ssirtuin_cat_dom
    PfamiView protein in Pfam
    PF02146 SIR2, 1 hit
    PIRSFiPIRSF037938 SIR2_euk, 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

    Isoform 1 (identifier: Q9NTG7-1) [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
    MAFWGWRAAA ALRLWGRVVE RVEAGGGVGP FQACGCRLVL GGRDDVSAGL
    60 70 80 90 100
    RGSHGARGEP LDPARPLQRP PRPEVPRAFR RQPRAAAPSF FFSSIKGGRR
    110 120 130 140 150
    SISFSVGASS VVGSGGSSDK GKLSLQDVAE LIRARACQRV VVMVGAGIST
    160 170 180 190 200
    PSGIPDFRSP GSGLYSNLQQ YDLPYPEAIF ELPFFFHNPK PFFTLAKELY
    210 220 230 240 250
    PGNYKPNVTH YFLRLLHDKG LLLRLYTQNI DGLERVSGIP ASKLVEAHGT
    260 270 280 290 300
    FASATCTVCQ RPFPGEDIRA DVMADRVPRC PVCTGVVKPD IVFFGEPLPQ
    310 320 330 340 350
    RFLLHVVDFP MADLLLILGT SLEVEPFASL TEAVRSSVPR LLINRDLVGP
    360 370 380 390
    LAWHPRSRDV AQLGDVVHGV ESLVELLGWT EEMRDLVQRE TGKLDGPDK
    Length:399
    Mass (Da):43,573
    Last modified:October 31, 2003 - v2
    Checksum:i4BA8BD3AC5FC7901
    GO
    Isoform 2 (identifier: Q9NTG7-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-142: Missing.

    Show »
    Length:257
    Mass (Da):28,567
    Checksum:i33043FAB6B3F0307
    GO

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_05197780R → W. Corresponds to variant dbSNP:rs28365927Ensembl.1
    Natural variantiVAR_051978208V → I. Corresponds to variant dbSNP:rs11246020Ensembl.1
    Natural variantiVAR_051979369G → S. Corresponds to variant dbSNP:rs3020901Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0437921 – 142Missing in isoform 2. 1 PublicationAdd BLAST142

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF083108 mRNA Translation: AAD40851.1
    AK299438 mRNA Translation: BAH13032.1
    AC136475 Genomic DNA No translation available.
    BC001042 mRNA Translation: AAH01042.1
    AL137276 mRNA Translation: CAB70674.1
    CCDSiCCDS53590.1 [Q9NTG7-2]
    CCDS7691.1 [Q9NTG7-1]
    PIRiT46348
    RefSeqiNP_001017524.1, NM_001017524.2 [Q9NTG7-2]
    NP_036371.1, NM_012239.5 [Q9NTG7-1]
    XP_016872919.1, XM_017017430.1 [Q9NTG7-2]
    UniGeneiHs.716456

    Genome annotation databases

    EnsembliENST00000382743; ENSP00000372191; ENSG00000142082 [Q9NTG7-1]
    ENST00000529382; ENSP00000437216; ENSG00000142082 [Q9NTG7-2]
    GeneIDi23410
    KEGGihsa:23410
    UCSCiuc001lok.5 human [Q9NTG7-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiSIR3_HUMAN
    AccessioniPrimary (citable) accession number: Q9NTG7
    Secondary accession number(s): B7Z5U6, Q9Y6E8
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2003
    Last sequence update: October 31, 2003
    Last modified: June 20, 2018
    This is version 157 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

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