Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q9Y6E7 (SIR4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
NAD-dependent protein deacetylase sirtuin-4

EC=3.5.1.-
Alternative name(s):
NAD-dependent ADP-ribosyltransferase sirtuin-4
EC=2.4.2.-
Regulatory protein SIR2 homolog 4
SIR2-like protein 4
Gene names
Name:SIRT4
Synonyms:SIR2L4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length314 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Acts both as NAD-dependent protein ADP-ribosyl transferase and NAD-dependent protein deacetylase. Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity. Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest. In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation. Acts as a tumor suppressor. Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis. Down-regulates insulin secretion. Ref.4 Ref.5 Ref.7 Ref.8

Catalytic activity

NAD+ + a protein = nicotinamide + an N-(ADP-D-ribosyl)-protein. HAMAP-Rule MF_03161

NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein. HAMAP-Rule MF_03161

Cofactor

Binds 1 zinc ion per subunit By similarity. HAMAP-Rule MF_03161

Subunit structure

Interacts with GLUD1, IDE and SLC25A5. Ref.4 Ref.5

Subcellular location

Mitochondrion matrix Ref.4 Ref.5 Ref.6.

Tissue specificity

Detected in vascular smooth muscle and striated muscle. Detected in insulin-producing beta-cells in pancreas islets of Langerhans (at protein level). Widely expressed. Weakly expressed in leukocytes and fetal thymus. Ref.1

Miscellaneous

Expression is down-regulated in a number of cancers, while overexpression reduces cell proliferation, transformation, and tumor development (Ref.7, Ref.8).

According to some authors, ADP-ribosyltransferase activity of sirtuins may be an inefficient side reaction of the deacetylase activity and may not be physiologically relevant By similarity.

Sequence similarities

Belongs to the sirtuin family. Class II subfamily.

Contains 1 deacetylase sirtuin-type domain.

Sequence caution

The sequence AAB95634.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
   Biological processDNA damage
   Cellular componentMitochondrion
   DiseaseTumor suppressor
   DomainTransit peptide
   LigandMetal-binding
NAD
Zinc
   Molecular functionHydrolase
Transferase
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processcellular response to DNA damage stimulus

Inferred from sequence or structural similarity. Source: UniProtKB

chromatin silencing

Traceable author statement Ref.1. Source: ProtInc

glutamine metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of fatty acid oxidation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of insulin secretion

Inferred from mutant phenotype Ref.5. Source: UniProtKB

peptidyl-lysine deacetylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of lipid biosynthetic process

Inferred from sequence or structural similarity. Source: UniProtKB

protein ADP-ribosylation

Inferred from sequence or structural similarity. Source: UniProtKB

tricarboxylic acid metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentmitochondrial matrix

Inferred from direct assay Ref.4Ref.5. Source: UniProtKB

mitochondrion

Inferred from direct assay Ref.6. Source: UniProtKB

   Molecular_functionNAD+ ADP-ribosyltransferase activity

Inferred from direct assay Ref.4Ref.5. Source: UniProtKB

NAD+ binding

Inferred from electronic annotation. Source: UniProtKB-HAMAP

hydrolase activity

Inferred from electronic annotation. Source: UniProtKB-HAMAP

protein binding

Inferred from physical interaction Ref.4Ref.5. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: UniProtKB-HAMAP

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

SLC25A5P051412EBI-2606540,EBI-355133

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 2828Mitochondrion Ref.4 Ref.5
Chain29 – 314286NAD-dependent protein deacetylase sirtuin-4 HAMAP-Rule MF_03161
PRO_0000110264

Regions

Domain45 – 314270Deacetylase sirtuin-type
Nucleotide binding62 – 8221NAD By similarity
Nucleotide binding143 – 1464NAD By similarity
Nucleotide binding260 – 2623NAD By similarity
Nucleotide binding286 – 2883NAD By similarity

Sites

Active site1611Proton acceptor By similarity
Metal binding1691Zinc By similarity
Metal binding1721Zinc By similarity
Metal binding2201Zinc By similarity
Metal binding2231Zinc By similarity
Binding site3041NAD; via amide nitrogen By similarity

Sequences

Sequence LengthMass (Da)Tools
Q9Y6E7 [UniParc].

Last modified November 1, 1999. Version 1.
Checksum: 2B76963AD2C3B354

FASTA31435,188
        10         20         30         40         50         60 
MKMSFALTFR SAKGRWIANP SQPCSKASIG LFVPASPPLD PEKVKELQRF ITLSKRLLVM 

        70         80         90        100        110        120 
TGAGISTESG IPDYRSEKVG LYARTDRRPI QHGDFVRSAP IRQRYWARNF VGWPQFSSHQ 

       130        140        150        160        170        180 
PNPAHWALST WEKLGKLYWL VTQNVDALHT KAGSRRLTEL HGCMDRVLCL DCGEQTPRGV 

       190        200        210        220        230        240 
LQERFQVLNP TWSAEAHGLA PDGDVFLSEE QVRSFQVPTC VQCGGHLKPD VVFFGDTVNP 

       250        260        270        280        290        300 
DKVDFVHKRV KEADSLLVVG SSLQVYSGYR FILTAWEKKL PIAILNIGPT RSDDLACLKL 

       310 
NSRCGELLPL IDPC 

« Hide

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], TISSUE SPECIFICITY.
Tissue: Testis.
[2]"The finished DNA sequence of human chromosome 12."
Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. expand/collapse author list , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A.
Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"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].
[4]"SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells."
Haigis M.C., Mostoslavsky R., Haigis K.M., Fahie K., Christodoulou D.C., Murphy A.J., Valenzuela D.M., Yancopoulos G.D., Karow M., Blander G., Wolberger C., Prolla T.A., Weindruch R., Alt F.W., Guarente L.
Cell 126:941-954(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, INTERACTION WITH GLUD1, SUBCELLULAR LOCATION.
[5]"Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase."
Ahuja N., Schwer B., Carobbio S., Waltregny D., North B.J., Castronovo V., Maechler P., Verdin E.
J. Biol. Chem. 282:33583-33592(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH IDE AND SLC25A5.
[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] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[7]"SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism."
Jeong S.M., Xiao C., Finley L.W., Lahusen T., Souza A.L., Pierce K., Li Y.H., Wang X., Laurent G., German N.J., Xu X., Li C., Wang R.H., Lee J., Csibi A., Cerione R., Blenis J., Clish C.B. expand/collapse author list , Kimmelman A., Deng C.X., Haigis M.C.
Cancer Cell 23:450-463(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS A TUMOR SUPPRESSOR.
[8]"The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4."
Csibi A., Fendt S.M., Li C., Poulogiannis G., Choo A.Y., Chapski D.J., Jeong S.M., Dempsey J.M., Parkhitko A., Morrison T., Henske E.P., Haigis M.C., Cantley L.C., Stephanopoulos G., Yu J., Blenis J.
Cell 153:840-854(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS A TUMOR SUPPRESSOR.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF083109 mRNA. Translation: AAD40852.1.
AC003982 Genomic DNA. Translation: AAB95634.1. Sequence problems.
BC109319 mRNA. Translation: AAI09320.1.
BC109320 mRNA. Translation: AAI09321.1.
CCDSCCDS9194.1.
RefSeqNP_036372.1. NM_012240.2.
XP_006719371.1. XM_006719308.1.
XP_006719372.1. XM_006719309.1.
XP_006719373.1. XM_006719310.1.
XP_006719374.1. XM_006719311.1.
UniGeneHs.50861.

3D structure databases

ProteinModelPortalQ9Y6E7.
SMRQ9Y6E7. Positions 42-311.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid116981. 8 interactions.
IntActQ9Y6E7. 5 interactions.
STRING9606.ENSP00000202967.

Chemistry

ChEMBLCHEMBL2163185.

PTM databases

PhosphoSiteQ9Y6E7.

Polymorphism databases

DMDM38258657.

Proteomic databases

PaxDbQ9Y6E7.
PRIDEQ9Y6E7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000202967; ENSP00000202967; ENSG00000089163.
GeneID23409.
KEGGhsa:23409.
UCSCuc001tyc.3. human.

Organism-specific databases

CTD23409.
GeneCardsGC12P120740.
HGNCHGNC:14932. SIRT4.
HPAHPA029691.
HPA029692.
MIM604482. gene.
neXtProtNX_Q9Y6E7.
PharmGKBPA37937.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0846.
HOGENOMHOG000085953.
HOVERGENHBG059577.
InParanoidQ9Y6E7.
KOK11414.
OMALCLNCGE.
PhylomeDBQ9Y6E7.
TreeFamTF106182.

Gene expression databases

ArrayExpressQ9Y6E7.
BgeeQ9Y6E7.
CleanExHS_SIRT4.
GenevestigatorQ9Y6E7.

Family and domain databases

Gene3D3.30.1600.10. 2 hits.
3.40.50.1220. 3 hits.
HAMAPMF_01967. Sirtuin_ClassII.
InterProIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom.
IPR026587. Sirtuin_class_II.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERPTHR11085. PTHR11085. 1 hit.
PfamPF02146. SIR2. 1 hit.
[Graphical view]
SUPFAMSSF52467. SSF52467. 1 hit.
PROSITEPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiSIRT4.
GenomeRNAi23409.
NextBio45593.
PROQ9Y6E7.
SOURCESearch...

Entry information

Entry nameSIR4_HUMAN
AccessionPrimary (citable) accession number: Q9Y6E7
Secondary accession number(s): O43346, Q32M33
Entry history
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: November 1, 1999
Last modified: July 9, 2014
This is version 114 of the entry and version 1 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

MIM cross-references

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

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM