Reviewed, UniProtKB/Swiss-Prot Q9NTG7 (SIRT3_HUMAN)

Names and origin

Protein names

Recommended name:
    NAD-dependent deacetylase sirtuin-3, mitochondrial
    EC=3.5.1.-
Alternative name(s):
    SIR2-like protein 3
      Short name=hSIRT3

Gene names

Name:	SIRT3
Synonyms:	SIR2L3

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	399 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels. Ref.7 Ref.9 Ref.10 Ref.11
Catalytic activity	NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein. Ref.7 Ref.4 Ref.5
Cofactor	Binds 1 zinc ion per subunit.
Subunit structure	Interacts with NDUFA9, ACSS1, IDH2 and GDH. Ref.7 Ref.10
Subcellular location	Mitochondrion matrix Ref.4 Ref.5 Ref.6 Ref.8.
Tissue specificity	Widely expressed. Ref.5 Ref.1
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. Contains 1 deacetylase sirtuin-type domain.
Biophysicochemical properties	Kinetic parameters: KM=600 µM for NAD

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Domain	Transit peptide
Ligand	Metal-binding NAD Zinc
Molecular function	Hydrolase
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	chromatin silencing Inferred from electronic annotation. Source: InterPro protein amino acid ADP-ribosylation Ref.1 Traceable author statement. Source: ProtInc protein amino acid deacetylation Ref.7 Inferred from direct assay. Source: UniProtKB
Cellular component	mitochondrial matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	NAD binding Inferred from electronic annotation. Source: InterPro NAD+ ADP-ribosyltransferase activity Ref.1 Traceable author statement. Source: ProtInc hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides Inferred from electronic annotation. Source: InterPro protein binding Ref.7 Ref.11 Inferred from physical interaction. Source: UniProtKB zinc ion binding Ref.11 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATP5A1	P25705	1	EBI-724621,EBI-351437
FOXO3	O43524	1	EBI-724621,EBI-1644164

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – ?

Mitochondrion Potential

Chain

? – 399

NAD-dependent deacetylase sirtuin-3, mitochondrial

PRO_0000032612

Regions

Domain

126 – 382

257

Deacetylase sirtuin-type

Nucleotide binding

145 – 165

21

NAD By similarity

Nucleotide binding

228 – 232

5

NAD By similarity

Sites

Active site

248

1

Proton acceptor

Metal binding

256

1

Zinc

Metal binding

259

1

Zinc

Metal binding

280

1

Zinc

Metal binding

283

1

Zinc

Natural variations

Natural variant

80

1

R → W: dbSNP rs28365927.

VAR_051977

Natural variant

208

1

V → I: dbSNP rs11246020.

VAR_051978

Natural variant

369

1

G → S: dbSNP rs3020901.

VAR_051979

Experimental info

Mutagenesis

7

1

R → G or Q: Suppresses targeting to mitochondrion; when associated with G-13 or Q-13. Ref.4

Mutagenesis

13

1

R → G or Q: Suppresses targeting to mitochondrion; when associated with G-7 or Q-7. Ref.4

Mutagenesis

17

1

R → G or Q: Reduces targeting to mitochondrion; when associated with G-21 or Q-21. Ref.4

Mutagenesis

21

1

R → G or Q: Reduces targeting to mitochondrion; when associated with G-17 or Q-17. Ref.4

Mutagenesis

99 – 100

2

RR → GG: Abolishes processing by MPP (in vitro).

Mutagenesis

229

1

N → A: Loss of function. Ref.4

Mutagenesis

248

1

H → Y: Loss of function. Ref.7 Ref.10 Ref.4

Secondary structure

1

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399

Helix Strand Turn

Details...

Helix

125 – 133

9

Beta strand

140 – 144

5

Helix

165 – 169

5

Helix

176 – 180

5

Helix

182 – 187

6

Helix

190 – 199

10

Helix

208 – 218

11

Beta strand

222 – 227

6

Turn

234 – 236

3

Helix

241 – 243

3

Beta strand

244 – 246

3

Beta strand

254 – 256

3

Turn

257 – 259

3

Helix

269 – 273

5

Turn

281 – 283

3

Beta strand

287 – 290

4

Helix

300 – 304

5

Helix

305 – 311

7

Beta strand

313 – 317

5

Helix

328 – 332

5

Beta strand

340 – 346

7

Turn

351 – 353

3

Beta strand

359 – 362

4

Helix

371 – 376

6

Helix

380 – 390

11

Sequences

	Sequence		Length	Mass (Da)
	Q9NTG7-1 [UniParc]. Last modified October 31, 2003. Version 2. Checksum: 4BA8BD3AC5FC7901	FASTA	399	43,573
	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

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]	"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]. Tissue: Lung.
[3]	"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: 17974005] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 282-399. Tissue: Testis.
[4]	"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: 12186850] [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.
[5]	"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: 12374852] [Abstract] Cited for: ENZYME ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[6]	"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: 16079181] [Abstract] Cited for: SUBCELLULAR LOCATION.
[7]	"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: 16788062] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-248, INTERACTION WITH ACSS1.
[8]	"The human SIRT3 protein deacetylase is exclusively mitochondrial." Cooper H.M., Spelbrink J.N. Biochem. J. 411:279-285(2008) [PubMed: 18215119] [Abstract] Cited for: SUBCELLULAR LOCATION.
[9]	"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: 18680753] [Abstract] Cited for: FUNCTION.
[10]	"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: 18794531] [Abstract] Cited for: MUTAGENESIS OF HIS-248, FUNCTION, INTERACTION WITH NDUFA9.
[11]	"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: 19535340] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 118-399 IN COMPLEX WITH ZINC IONS AND ACSS1, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, NAD BINDING.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF083108 mRNA. Translation: AAD40851.1.
BC001042 mRNA. Translation: AAH01042.1.
AL137276 mRNA. Translation: CAB70674.1.

IPI

IPI00183171.

PIR

T46348.

RefSeq

NP_001017524.1.
NP_036371.1.

UniGene

Hs.716456

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3GLR	X-ray	1.80	A	118-399	[»]
3GLS	X-ray	2.70	A/B/C/D/E/F	118-399	[»]
3GLT	X-ray	2.10	A	118-399	[»]
3GLU	X-ray	2.50	A	118-399	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9NTG7. 22 interactions.

STRING

Q9NTG7.

Proteomic databases

PRIDE

Q9NTG7.

Genome annotation databases

Ensembl

ENST00000382743; ENSP00000372191; ENSG00000142082; Homo sapiens. [Genome view]

GeneID

23410.

KEGG

hsa:23410.

UCSC

uc001lok.2. human.

Organism-specific databases

CTD

23410.

GeneCards

GC11M000206.

H-InvDB

HIX0009339.

HGNC

HGNC:14931. SIRT3.

MIM

604481. gene.

PharmGKB

PA37936.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG13093.

HOVERGEN

Q9NTG7.

InParanoid

Q9NTG7.

OMA

ERASGIP.

OrthoDB

EOG9J6V94.

PhylomeDB

Q9NTG7.

Enzyme and pathway databases

Pathway_Interaction_DB

hdac_classi_pathway. Signaling events mediated by HDAC Class I.
hdac_classiii_pathway. Signaling events mediated by HDAC Class III.

Gene expression databases

ArrayExpress

Q9NTG7.

Bgee

Q9NTG7.

CleanEx

HS_SIRT3.

Genevestigator

Q9NTG7.

GermOnline

ENSG00000142082. Homo sapiens.

Family and domain databases

InterPro

IPR017328. NAD-dep_deAcase_SIR2_euk.
IPR003000. NAD-dep_histone_deAcase_SIR2.
[Graphical view]

PANTHER

PTHR11085. SIR2. 1 hit.

Pfam

PF02146. SIR2. 1 hit.
[Graphical view]

PIRSF

PIRSF037938. SIR2_euk. 1 hit.

PROSITE

PS50305. SIRTUIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

45597.

SOURCE

Search...

Entry information

Entry name

SIRT3_HUMAN

Accession

Primary (citable) accession number: Q9NTG7
Secondary accession number(s): Q9Y6E8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 31, 2003
Last sequence update:	October 31, 2003
Last modified:	January 19, 2010
This is version 77 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.