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Protein

NAD-dependent protein lipoamidase sirtuin-4, mitochondrial

Gene

Sirt4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts as NAD-dependent protein lipoamidase, ADP-ribosyl transferase and deacetylase (PubMed:19220062). Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications. Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner (PubMed:25525879). 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 (PubMed:16959573). In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation (PubMed:23663782). Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782). 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 (PubMed:23746352). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation. Impairs SIRT1:PPARA interaction probably through the regulation of NAD+ levels (PubMed:24043310, PubMed:20685656). Down-regulates insulin secretion (By similarity).UniRule annotation7 Publications

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 sitei158 – 1581Proton acceptorUniRule annotation
Metal bindingi166 – 1661ZincUniRule annotation
Metal bindingi169 – 1691ZincUniRule annotation
Metal bindingi217 – 2171ZincUniRule annotation
Metal bindingi220 – 2201ZincUniRule annotation
Binding sitei301 – 3011NAD; via amide nitrogenUniRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi59 – 7921NADUniRule annotationAdd
BLAST
Nucleotide bindingi140 – 1434NADUniRule annotation
Nucleotide bindingi257 – 2593NADUniRule annotation
Nucleotide bindingi283 – 2853NADUniRule annotation

GO - Molecular functioni

  • biotinidase activity Source: UniProtKB
  • lipoamidase activity Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • NAD+ ADP-ribosyltransferase activity Source: UniProtKB
  • NAD+ binding Source: InterPro
  • NAD-dependent protein deacetylase activity Source: UniProtKB

GO - Biological processi

  • cellular response to DNA damage stimulus Source: UniProtKB
  • cellular response to hypoxia Source: Ensembl
  • glutamine metabolic process Source: UniProtKB
  • negative regulation of cardiac muscle cell apoptotic process Source: Ensembl
  • negative regulation of fatty acid oxidation Source: UniProtKB
  • negative regulation of insulin secretion Source: UniProtKB
  • negative regulation of protein processing involved in protein targeting to mitochondrion Source: Ensembl
  • peptidyl-lysine deacetylation Source: UniProtKB
  • positive regulation of lipid biosynthetic process Source: UniProtKB
  • protein ADP-ribosylation Source: UniProtKB
  • regulation of glutamine family amino acid metabolic process Source: CACAO
  • regulation of pyruvate dehydrogenase activity Source: UniProtKB
  • 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 lipoamidase sirtuin-4, mitochondrial1 PublicationUniRule annotation (EC:3.5.1.-UniRule annotation1 Publication)
Alternative name(s):
NAD-dependent ADP-ribosyltransferase sirtuin-4UniRule annotation (EC:2.4.2.-UniRule annotation)
NAD-dependent protein deacetylase sirtuin-4UniRule annotation (EC:3.5.1.-UniRule annotation)
Regulatory protein SIR2 homolog 4UniRule annotation
SIR2-like protein 4UniRule annotation
Gene namesi
Name:Sirt4
Synonyms:Sir2l4
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 5

Organism-specific databases

MGIiMGI:1922637. Sirt4.

Subcellular locationi

GO - Cellular componenti

  • mitochondrial inner membrane Source: CACAO
  • mitochondrial matrix Source: UniProtKB
  • mitochondrion Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Disruption phenotypei

No visible phenotype. Decreased mitochondrial protein ADP-ribosylation. Increased plasma insulin levels. Mice develop lung tumors more frequently. Defects in lipid metabolism, leading to increased protection against diet-induced obesity. Animals show higher levels of NAD+ in liver (PubMed:24043310). In the hepatic periportal zone, decreased number of mitochondria with an increase in their length (PubMed:24043310).4 Publications

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transit peptidei1 – 2525MitochondrionUniRule annotationAdd
BLAST
Chaini26 – 333308NAD-dependent protein lipoamidase sirtuin-4, mitochondrialPRO_0000110265Add
BLAST

Proteomic databases

EPDiQ8R216.
MaxQBiQ8R216.
PaxDbiQ8R216.
PRIDEiQ8R216.

PTM databases

PhosphoSiteiQ8R216.

Expressioni

Tissue specificityi

Detected in kidney, heart, brain, liver and pancreatic islets (at protein level).1 Publication

Inductioni

Expression is directly activated by ATF4/CREB2. In response to mTORC1 signal, expression is down-regulated due to degradation of ATF4/CREB2 (PubMed:23663782). Induced following DNA damage (PubMed:23562301). The expression is strongly inhibited by fasting (PubMed:24043310).3 Publications

Gene expression databases

BgeeiQ8R216.
GenevisibleiQ8R216. MM.

Interactioni

Subunit structurei

Interacts with IDE and SLC25A5 (By similarity). Interacts with GLUD1. Interacts with DLAT and PDHX (By similarity).By similarity1 Publication

Protein-protein interaction databases

BioGridi217445. 1 interaction.
STRINGi10090.ENSMUSP00000107697.

Structurei

3D structure databases

ProteinModelPortaliQ8R216.
SMRiQ8R216. Positions 23-305.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini42 – 317276Deacetylase 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

eggNOGiKOG2683. Eukaryota.
COG0846. LUCA.
GeneTreeiENSGT00740000115330.
HOGENOMiHOG000085953.
HOVERGENiHBG059577.
InParanoidiQ8R216.
KOiK11414.
OMAiCSKASIG.
OrthoDBiEOG7DZ8KF.
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. 2 hits.
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.

Q8R216-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSGLTFRPTK GRWITHLSRP RSCGPSGLFV PPSPPLDPEK IKELQRFISL
60 70 80 90 100
SKKLLVMTGA GISTESGIPD YRSEKVGLYA RTDRRPIQHI DFVRSAPVRQ
110 120 130 140 150
RYWARNFVGW PQFSSHQPNP AHWALSNWER LGKLHWLVTQ NVDALHSKAG
160 170 180 190 200
SQRLTELHGC MHRVLCLNCG EQTARRVLQE RFQALNPSWS AEAQGVAPDG
210 220 230 240 250
DVFLTEEQVR SFQVPCCDRC GGPLKPDVVF FGDTVNPDKV DFVHRRVKEA
260 270 280 290 300
DSLLVVGSSL QVYSGYRFIL TAREQKLPIA ILNIGPTRSD DLACLKLDSR
310 320 330
CGELLPLIDP RRQHSDVQRL EMNFPLSSAA QDP
Length:333
Mass (Da):37,525
Last modified:July 27, 2011 - v3
Checksum:iAD9FBB1CC217D05E
GO

Sequence cautioni

The sequence AAH22653.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti67 – 671G → S in AAH22653 (Ref. 2) Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AC117735 Genomic DNA. No translation available.
AC159539 Genomic DNA. No translation available.
CH466529 Genomic DNA. Translation: EDL19856.1.
CH466529 Genomic DNA. Translation: EDL19857.1.
BC022653 mRNA. Translation: AAH22653.1. Different initiation.
CCDSiCCDS51628.1.
RefSeqiNP_001161163.1. NM_001167691.1.
NP_598521.1. NM_133760.1.
UniGeneiMm.332616.

Genome annotation databases

EnsembliENSMUST00000112066; ENSMUSP00000107697; ENSMUSG00000029524.
ENSMUST00000112067; ENSMUSP00000107698; ENSMUSG00000029524.
GeneIDi75387.
KEGGimmu:75387.
UCSCiuc008zdy.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AC117735 Genomic DNA. No translation available.
AC159539 Genomic DNA. No translation available.
CH466529 Genomic DNA. Translation: EDL19856.1.
CH466529 Genomic DNA. Translation: EDL19857.1.
BC022653 mRNA. Translation: AAH22653.1. Different initiation.
CCDSiCCDS51628.1.
RefSeqiNP_001161163.1. NM_001167691.1.
NP_598521.1. NM_133760.1.
UniGeneiMm.332616.

3D structure databases

ProteinModelPortaliQ8R216.
SMRiQ8R216. Positions 23-305.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi217445. 1 interaction.
STRINGi10090.ENSMUSP00000107697.

PTM databases

PhosphoSiteiQ8R216.

Proteomic databases

EPDiQ8R216.
MaxQBiQ8R216.
PaxDbiQ8R216.
PRIDEiQ8R216.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000112066; ENSMUSP00000107697; ENSMUSG00000029524.
ENSMUST00000112067; ENSMUSP00000107698; ENSMUSG00000029524.
GeneIDi75387.
KEGGimmu:75387.
UCSCiuc008zdy.1. mouse.

Organism-specific databases

CTDi23409.
MGIiMGI:1922637. Sirt4.

Phylogenomic databases

eggNOGiKOG2683. Eukaryota.
COG0846. LUCA.
GeneTreeiENSGT00740000115330.
HOGENOMiHOG000085953.
HOVERGENiHBG059577.
InParanoidiQ8R216.
KOiK11414.
OMAiCSKASIG.
OrthoDBiEOG7DZ8KF.
TreeFamiTF106182.

Miscellaneous databases

ChiTaRSiSirt4. mouse.
PROiQ8R216.
SOURCEiSearch...

Gene expression databases

BgeeiQ8R216.
GenevisibleiQ8R216. MM.

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. 2 hits.
PfamiPF02146. SIR2. 1 hit.
[Graphical view]
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  2. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
    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].
    Tissue: Colon.
  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: DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, INTERACTION WITH GLUD1, TISSUE SPECIFICITY.
  5. "Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and 32P-NAD."
    Du J., Jiang H., Lin H.
    Biochemistry 48:2878-2890(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  6. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Heart and Kidney.
  7. "SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells."
    Nasrin N., Wu X., Fortier E., Feng Y., Bare' O.C., Chen S., Ren X., Wu Z., Streeper R.S., Bordone L.
    J. Biol. Chem. 285:31995-32002(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. "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, DISRUPTION PHENOTYPE, INDUCTION.
  9. Cited for: FUNCTION, INDUCTION.
  10. "SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation."
    Laurent G., de Boer V.C., Finley L.W., Sweeney M., Lu H., Schug T.T., Cen Y., Jeong S.M., Li X., Sauve A.A., Haigis M.C.
    Mol. Cell. Biol. 33:4552-4561(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE, INDUCTION BY FASTING.
  11. Cited for: FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE.
  12. "Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity."
    Mathias R.A., Greco T.M., Oberstein A., Budayeva H.G., Chakrabarti R., Rowland E.A., Kang Y., Shenk T., Cristea I.M.
    Cell 159:1615-1625(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.

Entry informationi

Entry nameiSIR4_MOUSE
AccessioniPrimary (citable) accession number: Q8R216
Secondary accession number(s): D3Z1D9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: July 27, 2011
Last modified: June 8, 2016
This is version 107 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

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.1 Publication

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

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 one 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.