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Protein

NAD-dependent protein deacetylase sirtuin-4

Gene

SIRT4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.4 PublicationsUniRule annotation

Catalytic activityi

NAD+ + a protein = nicotinamide + an N-(ADP-D-ribosyl)-protein.UniRule annotation
NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein.UniRule annotation

Cofactori

Zn2+UniRule annotationNote: Binds 1 zinc ion per subunit.UniRule annotation

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei161 – 1611Proton acceptorUniRule annotation
Metal bindingi169 – 1691ZincUniRule annotation
Metal bindingi172 – 1721ZincUniRule annotation
Metal bindingi220 – 2201ZincUniRule annotation
Metal bindingi223 – 2231ZincUniRule annotation
Binding sitei304 – 3041NAD; via amide nitrogenUniRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi62 – 8221NADUniRule annotationAdd
BLAST
Nucleotide bindingi143 – 1464NADUniRule annotation
Nucleotide bindingi260 – 2623NADUniRule annotation
Nucleotide bindingi286 – 2883NADUniRule annotation

GO - Molecular functioni

  1. hydrolase activity Source: UniProtKB-HAMAP
  2. NAD+ ADP-ribosyltransferase activity Source: UniProtKB
  3. NAD+ binding Source: UniProtKB-HAMAP
  4. zinc ion binding Source: UniProtKB-HAMAP

GO - Biological processi

  1. cellular response to DNA damage stimulus Source: UniProtKB
  2. chromatin silencing Source: ProtInc
  3. glutamine metabolic process Source: UniProtKB
  4. negative regulation of fatty acid oxidation Source: UniProtKB
  5. negative regulation of insulin secretion Source: UniProtKB
  6. peptidyl-lysine deacetylation Source: UniProtKB
  7. positive regulation of lipid biosynthetic process Source: UniProtKB
  8. protein ADP-ribosylation Source: UniProtKB
  9. tricarboxylic acid metabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Transferase

Keywords - Biological processi

DNA damage

Keywords - Ligandi

Metal-binding, NAD, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
NAD-dependent protein deacetylase sirtuin-4UniRule annotation (EC:3.5.1.-UniRule annotation)
Alternative name(s):
NAD-dependent ADP-ribosyltransferase sirtuin-4UniRule annotation (EC:2.4.2.-UniRule annotation)
Regulatory protein SIR2 homolog 4UniRule annotation
SIR2-like protein 4UniRule annotation
Gene namesi
Name:SIRT4UniRule annotation
Synonyms:SIR2L4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 12

Organism-specific databases

HGNCiHGNC:14932. SIRT4.

Subcellular locationi

Mitochondrion matrix 3 PublicationsUniRule annotation

GO - Cellular componenti

  1. mitochondrial matrix Source: UniProtKB
  2. mitochondrion Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Keywords - Diseasei

Tumor suppressor

Organism-specific databases

PharmGKBiPA37937.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transit peptidei1 – 2828Mitochondrion2 PublicationsUniRule annotationAdd
BLAST
Chaini29 – 314286NAD-dependent protein deacetylase sirtuin-4PRO_0000110264Add
BLAST

Proteomic databases

PaxDbiQ9Y6E7.
PRIDEiQ9Y6E7.

PTM databases

PhosphoSiteiQ9Y6E7.

Expressioni

Tissue specificityi

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.1 Publication

Gene expression databases

BgeeiQ9Y6E7.
CleanExiHS_SIRT4.
ExpressionAtlasiQ9Y6E7. baseline and differential.
GenevestigatoriQ9Y6E7.

Organism-specific databases

HPAiHPA029691.
HPA029692.

Interactioni

Subunit structurei

Interacts with GLUD1, IDE and SLC25A5.2 PublicationsUniRule annotation

Binary interactionsi

WithEntry#Exp.IntActNotes
SLC25A5P051412EBI-2606540,EBI-355133

Protein-protein interaction databases

BioGridi116981. 10 interactions.
IntActiQ9Y6E7. 5 interactions.
STRINGi9606.ENSP00000202967.

Structurei

3D structure databases

ProteinModelPortaliQ9Y6E7.
SMRiQ9Y6E7. Positions 42-311.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini45 – 314270Deacetylase sirtuin-typeUniRule annotationAdd
BLAST

Sequence similaritiesi

Belongs to the sirtuin family. Class II subfamily.UniRule annotation
Contains 1 deacetylase sirtuin-type domain.UniRule annotation

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiCOG0846.
GeneTreeiENSGT00740000115330.
HOGENOMiHOG000085953.
HOVERGENiHBG059577.
InParanoidiQ9Y6E7.
KOiK11414.
OMAiTPRGVLQ.
PhylomeDBiQ9Y6E7.
TreeFamiTF106182.

Family and domain databases

Gene3Di3.30.1600.10. 2 hits.
3.40.50.1220. 3 hits.
HAMAPiMF_01967. Sirtuin_ClassII.
InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom.
IPR026587. Sirtuin_class_II.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERiPTHR11085. PTHR11085. 1 hit.
PfamiPF02146. SIR2. 1 hit.
[Graphical view]
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiPS50305. SIRTUIN. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9Y6E7-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MKMSFALTFR SAKGRWIANP SQPCSKASIG LFVPASPPLD PEKVKELQRF
60 70 80 90 100
ITLSKRLLVM TGAGISTESG IPDYRSEKVG LYARTDRRPI QHGDFVRSAP
110 120 130 140 150
IRQRYWARNF VGWPQFSSHQ PNPAHWALST WEKLGKLYWL VTQNVDALHT
160 170 180 190 200
KAGSRRLTEL HGCMDRVLCL DCGEQTPRGV LQERFQVLNP TWSAEAHGLA
210 220 230 240 250
PDGDVFLSEE QVRSFQVPTC VQCGGHLKPD VVFFGDTVNP DKVDFVHKRV
260 270 280 290 300
KEADSLLVVG SSLQVYSGYR FILTAWEKKL PIAILNIGPT RSDDLACLKL
310
NSRCGELLPL IDPC
Length:314
Mass (Da):35,188
Last modified:November 1, 1999 - v1
Checksum:i2B76963AD2C3B354
GO

Sequence cautioni

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

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF083109 mRNA. Translation: AAD40852.1.
AC003982 Genomic DNA. Translation: AAB95634.1. Sequence problems.
BC109319 mRNA. Translation: AAI09320.1.
BC109320 mRNA. Translation: AAI09321.1.
CCDSiCCDS9194.1.
RefSeqiNP_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.
UniGeneiHs.50861.

Genome annotation databases

EnsembliENST00000202967; ENSP00000202967; ENSG00000089163.
GeneIDi23409.
KEGGihsa:23409.
UCSCiuc001tyc.3. human.

Polymorphism databases

DMDMi38258657.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF083109 mRNA. Translation: AAD40852.1.
AC003982 Genomic DNA. Translation: AAB95634.1. Sequence problems.
BC109319 mRNA. Translation: AAI09320.1.
BC109320 mRNA. Translation: AAI09321.1.
CCDSiCCDS9194.1.
RefSeqiNP_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.
UniGeneiHs.50861.

3D structure databases

ProteinModelPortaliQ9Y6E7.
SMRiQ9Y6E7. Positions 42-311.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116981. 10 interactions.
IntActiQ9Y6E7. 5 interactions.
STRINGi9606.ENSP00000202967.

Chemistry

ChEMBLiCHEMBL2163185.

PTM databases

PhosphoSiteiQ9Y6E7.

Polymorphism databases

DMDMi38258657.

Proteomic databases

PaxDbiQ9Y6E7.
PRIDEiQ9Y6E7.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000202967; ENSP00000202967; ENSG00000089163.
GeneIDi23409.
KEGGihsa:23409.
UCSCiuc001tyc.3. human.

Organism-specific databases

CTDi23409.
GeneCardsiGC12P120740.
HGNCiHGNC:14932. SIRT4.
HPAiHPA029691.
HPA029692.
MIMi604482. gene.
neXtProtiNX_Q9Y6E7.
PharmGKBiPA37937.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0846.
GeneTreeiENSGT00740000115330.
HOGENOMiHOG000085953.
HOVERGENiHBG059577.
InParanoidiQ9Y6E7.
KOiK11414.
OMAiTPRGVLQ.
PhylomeDBiQ9Y6E7.
TreeFamiTF106182.

Miscellaneous databases

GeneWikiiSIRT4.
GenomeRNAii23409.
NextBioi45593.
PROiQ9Y6E7.
SOURCEiSearch...

Gene expression databases

BgeeiQ9Y6E7.
CleanExiHS_SIRT4.
ExpressionAtlasiQ9Y6E7. baseline and differential.
GenevestigatoriQ9Y6E7.

Family and domain databases

Gene3Di3.30.1600.10. 2 hits.
3.40.50.1220. 3 hits.
HAMAPiMF_01967. Sirtuin_ClassII.
InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom.
IPR026587. Sirtuin_class_II.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERiPTHR11085. PTHR11085. 1 hit.
PfamiPF02146. SIR2. 1 hit.
[Graphical view]
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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.
    , 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.
    , 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. Cited for: FUNCTION AS A TUMOR SUPPRESSOR.

Entry informationi

Entry nameiSIR4_HUMAN
AccessioniPrimary (citable) accession number: Q9Y6E7
Secondary accession number(s): O43346, Q32M33
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: November 1, 1999
Last modified: January 7, 2015
This is version 118 of the entry and version 1 of the sequence. [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

Miscellaneous

Expression is down-regulated in a number of cancers, while overexpression reduces cell proliferation, transformation, and tumor development (PubMed:23562301, PubMed:23663782).2 Publications
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.UniRule annotation

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.