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Q9NTG7 (SIR3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 119. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
NAD-dependent protein deacetylase sirtuin-3, mitochondrial

Short name=hSIRT3
EC=3.5.1.-
Alternative name(s):
Regulatory protein SIR2 homolog 3
SIR2-like protein 3
Gene names
Name:SIRT3
Synonyms:SIR2L3
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length399 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

NAD-dependent protein deacetylase. Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues. Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5O. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels. Ref.9 Ref.11 Ref.12 Ref.14 Ref.15 Ref.16

Catalytic activity

NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein. Ref.6 Ref.7 Ref.9

Cofactor

Binds 1 zinc ion per subunit.

Subunit structure

Interacts with NDUFA9, ACSS1, IDH2 and GDH. Ref.9 Ref.12

Subcellular location

Mitochondrion matrix Ref.6 Ref.7 Ref.8 Ref.10.

Tissue specificity

Widely expressed. Ref.1 Ref.7

Post-translational modification

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

Miscellaneous

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

Sequence similarities

Belongs to the sirtuin family. Class I subfamily.

Contains 1 deacetylase sirtuin-type domain.

Biophysicochemical properties

Kinetic parameters:

KM=600 µM for NAD Ref.16

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ATP5A1P257052EBI-724621,EBI-351437
SKP2Q133095EBI-724621,EBI-456291

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9NTG7-1)

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.
Isoform 2 (identifier: Q9NTG7-2)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – ?Mitochondrion Potential
Chain? – 399NAD-dependent protein deacetylase sirtuin-3, mitochondrialPRO_0000032612

Regions

Domain126 – 382257Deacetylase sirtuin-type
Nucleotide binding145 – 16521NAD
Nucleotide binding228 – 2314NAD
Nucleotide binding319 – 3213NAD
Nucleotide binding344 – 3463NAD

Sites

Active site2481Proton acceptor
Metal binding2561Zinc
Metal binding2591Zinc
Metal binding2801Zinc
Metal binding2831Zinc
Binding site3661NAD; via amide nitrogen By similarity

Natural variations

Alternative sequence1 – 142142Missing in isoform 2.
VSP_043792
Natural variant801R → W.
Corresponds to variant rs28365927 [ dbSNP | Ensembl ].
VAR_051977
Natural variant2081V → I.
Corresponds to variant rs11246020 [ dbSNP | Ensembl ].
VAR_051978
Natural variant3691G → S.
Corresponds to variant rs3020901 [ dbSNP | Ensembl ].
VAR_051979

Experimental info

Mutagenesis71R → G or Q: Suppresses targeting to mitochondrion; when associated with G-13 or Q-13. Ref.6
Mutagenesis131R → G or Q: Suppresses targeting to mitochondrion; when associated with G-7 or Q-7. Ref.6
Mutagenesis171R → G or Q: Reduces targeting to mitochondrion; when associated with G-21 or Q-21. Ref.6
Mutagenesis211R → G or Q: Reduces targeting to mitochondrion; when associated with G-17 or Q-17. Ref.6
Mutagenesis99 – 1002RR → GG: Abolishes processing by MPP (in vitro).
Mutagenesis2291N → A: Loss of function. Ref.6
Mutagenesis2481H → Y: Loss of function. Ref.6 Ref.9 Ref.12

Secondary structure

........................................................... 399
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 31, 2003. Version 2.
Checksum: 4BA8BD3AC5FC7901

FASTA39943,573
        10         20         30         40         50         60 
MAFWGWRAAA ALRLWGRVVE RVEAGGGVGP FQACGCRLVL GGRDDVSAGL RGSHGARGEP 

        70         80         90        100        110        120 
LDPARPLQRP PRPEVPRAFR RQPRAAAPSF FFSSIKGGRR SISFSVGASS VVGSGGSSDK 

       130        140        150        160        170        180 
GKLSLQDVAE LIRARACQRV VVMVGAGIST PSGIPDFRSP GSGLYSNLQQ YDLPYPEAIF 

       190        200        210        220        230        240 
ELPFFFHNPK PFFTLAKELY PGNYKPNVTH YFLRLLHDKG LLLRLYTQNI DGLERVSGIP 

       250        260        270        280        290        300 
ASKLVEAHGT FASATCTVCQ RPFPGEDIRA DVMADRVPRC PVCTGVVKPD IVFFGEPLPQ 

       310        320        330        340        350        360 
RFLLHVVDFP MADLLLILGT SLEVEPFASL TEAVRSSVPR LLINRDLVGP LAWHPRSRDV 

       370        380        390 
AQLGDVVHGV ESLVELLGWT EEMRDLVQRE TGKLDGPDK 

« Hide

Isoform 2 [UniParc].

Checksum: 33043FAB6B3F0307
Show »

FASTA25728,567

References

« Hide '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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
Tissue: Testis.
[2]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Tongue.
[3]"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. expand/collapse author list , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Lung.
[5]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 282-399 (ISOFORM 1).
Tissue: Testis.
[6]"The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase."
Schwer B., North B.J., Frye R.A., Ott M., Verdin E.
J. Cell Biol. 158:647-657(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME ACTIVITY, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING BY MPP, MUTAGENESIS OF ARG-7; ARG-13; ARG-17; ARG-21; 99-ARG-ARG-100; ASN-229 AND HIS-248.
[7]"SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria."
Onyango P., Celic I., McCaffery J.M., Boeke J.D., Feinberg A.P.
Proc. Natl. Acad. Sci. U.S.A. 99:13653-13658(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[8]"Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins."
Michishita E., Park J.Y., Burneskis J.M., Barrett J.C., Horikawa I.
Mol. Biol. Cell 16:4623-4635(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[9]"Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2."
Schwer B., Bunkenborg J., Verdin R.O., Andersen J.S., Verdin E.
Proc. Natl. Acad. Sci. U.S.A. 103:10224-10229(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-248, INTERACTION WITH ACSS1.
[10]"The human SIRT3 protein deacetylase is exclusively mitochondrial."
Cooper H.M., Spelbrink J.N.
Biochem. J. 411:279-285(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[11]"Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5."
Schlicker C., Gertz M., Papatheodorou P., Kachholz B., Becker C.F.W., Steegborn C.
J. Mol. Biol. 382:790-801(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[12]"A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis."
Ahn B.-H., Kim H.-S., Song S., Lee I.H., Liu J., Vassilopoulos A., Deng C.-X., Finkel T.
Proc. Natl. Acad. Sci. U.S.A. 105:14447-14452(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF HIS-248, FUNCTION, INTERACTION WITH NDUFA9.
[13]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[14]"SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient and exercise-induced stress."
Vassilopoulos A., Pennington D.J., Andresson T., Rees D., Fearnley I., Ham A., Yan Y., Flynn C.R., Jones K., Kim H.S., Deng C., Walker J., Gius D.
Antioxid. Redox Signal. 0:0-0(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[15]"SIRT3 regulates long-chain acyl-coA dehydrogenase by deacetylating conserved lysines near the active site."
Bharathi S.S., Zhang Y., Mohsen A.W., Uppala R., Balasubramani M., Schreiber E., Uechi G., Beck M.E., Rardin M.J., Vockley J., Verdin E., Gibson B.W., Hirschey M.D., Goetzman E.S.
J. Biol. Chem. 288:33837-33847(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[16]"Crystal structures of human SIRT3 displaying substrate-induced conformational changes."
Jin L., Wei W., Jiang Y., Peng H., Cai J., Mao C., Dai H., Choy W., Bemis J.E., Jirousek M.R., Milne J.C., Westphal C.H., Perni R.B.
J. Biol. Chem. 284:24394-24405(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 118-399 IN COMPLEX WITH ZINC IONS AND ACSS1, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, NAD-BINDING.
[17]"Structures of human sirtuin 3 complexes with ADP-ribose and with carba-NAD+ and SRT1720: binding details and inhibition mechanism."
Nguyen G.T., Schaefer S., Gertz M., Weyand M., Steegborn C.
Acta Crystallogr. D 69:1423-1432(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF 116-399 IN COMPLEX WITH INHIBITOR, NAD-BINDING SITES, ZINC-BINDING SITES.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS53590.1. [Q9NTG7-2]
CCDS7691.1. [Q9NTG7-1]
PIRT46348.
RefSeqNP_001017524.1. NM_001017524.2. [Q9NTG7-2]
NP_036371.1. NM_012239.5. [Q9NTG7-1]
UniGeneHs.716456.

3D structure databases

PDBe
RCSB-PDB
PDBj
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[»]
ProteinModelPortalQ9NTG7.
SMRQ9NTG7. Positions 121-394.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid116982. 94 interactions.
DIPDIP-46861N.
IntActQ9NTG7. 26 interactions.
MINTMINT-4540133.
STRING9606.ENSP00000372191.

Chemistry

BindingDBQ9NTG7.
ChEMBLCHEMBL4461.

PTM databases

PhosphoSiteQ9NTG7.

Polymorphism databases

DMDM38258651.

Proteomic databases

MaxQBQ9NTG7.
PaxDbQ9NTG7.
PRIDEQ9NTG7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000382743; ENSP00000372191; ENSG00000142082. [Q9NTG7-1]
ENST00000529382; ENSP00000437216; ENSG00000142082. [Q9NTG7-2]
GeneID23410.
KEGGhsa:23410.
UCSCuc001loj.4. human. [Q9NTG7-1]

Organism-specific databases

CTD23410.
GeneCardsGC11M000241.
HGNCHGNC:14931. SIRT3.
HPACAB037142.
HPA026809.
MIM604481. gene.
neXtProtNX_Q9NTG7.
PharmGKBPA37936.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0846.
HOVERGENHBG057095.
InParanoidQ9NTG7.
KOK11413.
OMALAWHPRS.
OrthoDBEOG7WX09C.
PhylomeDBQ9NTG7.
TreeFamTF106181.

Enzyme and pathway databases

ReactomeREACT_200751. Organelle biogenesis and maintenance.

Gene expression databases

ArrayExpressQ9NTG7.
BgeeQ9NTG7.
CleanExHS_SIRT3.
GenevestigatorQ9NTG7.

Family and domain databases

Gene3D3.30.1600.10. 2 hits.
3.40.50.1220. 3 hits.
InterProIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom.
IPR017328. Sirtuin_class_I.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERPTHR11085. PTHR11085. 1 hit.
PfamPF02146. SIR2. 1 hit.
[Graphical view]
PIRSFPIRSF037938. SIR2_euk. 1 hit.
SUPFAMSSF52467. SSF52467. 1 hit.
PROSITEPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSSIRT3. human.
EvolutionaryTraceQ9NTG7.
GeneWikiSIRT3.
GenomeRNAi23410.
NextBio45597.
PROQ9NTG7.
SOURCESearch...

Entry information

Entry nameSIR3_HUMAN
AccessionPrimary (citable) accession number: Q9NTG7
Secondary accession number(s): B7Z5U6, Q9Y6E8
Entry history
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 31, 2003
Last modified: July 9, 2014
This is version 119 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM