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

Q5RJQ4 (SIR2_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 83. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
NAD-dependent protein deacetylase sirtuin-2

EC=3.5.1.-
Alternative name(s):
Regulatory protein SIR2 homolog 2
SIR2-like protein 2
Gene names
Name:Sirt2
Synonyms:Sir2l2
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length350 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors. Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates with both chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by SETD8 leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates SETD8 modulating SETD8 chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition. During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-330 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagy. Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation. Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor. Ref.4 Ref.5 Ref.6

Catalytic activity

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

Cofactor

Binds 1 zinc ion per subunit By similarity.

Enzyme regulation

Inhibited by Sirtinol, A3 and M15 small molecules. Inhibited by nicotinamide. Inhibited by a macrocyclic peptide inhibitor S2iL5. Inhibited by EP300-induced acetylation By similarity.

Subunit structure

Homotrimer. Interacts (via both phosphorylated, unphosphorylated, active or inactive forms) with HDAC6; the interaction is necessary for the complex to interact with alpha-tubulin, suggesting that these proteins belong to a large complex that deacetylates the cytoskeleton. Interacts with FOXO1; the interaction is disrupted upon serum-starvation or oxidative stress, leading to increased level of acetylated FOXO1 and induction of autophagy. Interacts with RELA; the interaction occurs in the cytoplasm and is increased in a TNF-alpha-dependent manner. Interacts with HOXA10; the interaction is direct. Interacts with YWHAB and YWHAG; the interactions occur in a AKT-dependent manner and increase SIRT2-dependent TP53 deacetylation. Interacts with MAPK1/ERK2 and MAPK3/ERK1; the interactions increase SIRT2 stability and deacetylation activity. Interacts (phosphorylated form) with SETD8; the interaction is direct, stimulates SETD8-mediated methyltransferase activity on histone at 'Lys-20' (H4K20me1) and is increased in a H2O(2)-induced oxidative stress-dependent manner. Interacts with G6PD; the interaction is enhanced by H2O2 treatment. Interacts (via C-terminus region) with EP300. Interacts with a G1/S-specific cyclin E-CDK2 complex. Interacts with AURKA, CDC20, CDK5R1 (p35 form), CDK5, FOXO3, FZR1 and HIF1A. Associates with microtubule in primary cortical mature neurons By similarity.

Subcellular location

Nucleus By similarity. Cytoplasm. Cytoplasmperinuclear region. Perikaryon. Myelin membrane. Cell projection. Cytoplasmcytoskeleton. Cell projectiongrowth cone By similarity. Myelin membrane By similarity. Cytoplasmcytoskeletonmicrotubule organizing centercentrosome By similarity. Cytoplasmcytoskeletonspindle By similarity. Chromosome By similarity. Cytoplasmcytoskeletonmicrotubule organizing centercentrosomecentriole By similarity. Midbody By similarity. Note: Localizes in the cytoplasm during most of the cell cycle except in the G2/M transition and during mitosis, where it is localized in association with chromatin and induces deacetylation of histone at 'Lys-16' (H4K16ac). Colocalizes with CDK1 at centrosome during prophase and splindle fibers during metaphase. Colocalizes with Aurora kinase AURKA in centrioles during early prophase and growing mitotic spindle throughout metaphase. Colocalizes with Aurora kinase AURKB during cytokinesis with the midbody. Detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins. Shuttles between the cytoplasm and the nucleus through the CRM1 export pathway. Colocalizes with EP300 in the nucleus. Deacetylates FOXO3 in the cytoplasm. Colocalizes with Aurora kinase AURKA at centrosome. Colocalizes with microtubules. Colocalizes with CDK5R1 in the perikaryon, neurites and growth cone of hippocampal neurons. Colocalizes with alpha-tubulin in neuronal growth cone. Colocalizes with SETD8 at mitotic foci. Localizes in the cytoplasm and nucleus of germinal vesicle (GV) stage oocytes. Colocalizes with alpha-tubulin on the meiotic spindle as the oocytes enter into metaphase, and also during meiotic anaphase and telophase, especially with the midbody By similarity. Colocalizes with PLP1 in internodal regions of myelin sheat, at paranodal axoglial junction and Schmidt-Lanterman (SL) incisures. Colocalizes with PARD3 in internodal region of axons. Colocalizes with acetylated alpha-tubulin in cell projection processes during primary oligodendrocyte precursor (OLP) differentiation. Ref.4 Ref.5

Tissue specificity

Expressed in the cerebellum, cerebral cortex and cervival spinal cord. Expressed in Purkinje cells, oligodendrocytes and Schwann cells (at protein level). Expressed in the central nervous system (CNS). Ref.4 Ref.5

Induction

In oligodendrocytes during differentiation of CG-4 cells. Ref.3

Post-translational modification

Phosphorylated at phosphoserine and phosphothreonine. Phosphorylated at Ser-330 by a mitotic kinase CDK1/cyclin B at the G2/M transition; phosphorylation regulates the delay in cell-cycle progression. Phosphorylated at Ser-330 by a mitotic kinase G1/S-specific cyclin E/Cdk2 complex; phosphorylation inactivates SIRT2-mediated alpha-tubulin deacetylation and thereby negatively regulates cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Phosphorylated by cyclin A/Cdk2 and p35-Cdk5 complexes and to a lesser extent by the cyclin D3/Cdk4 and cyclin B/Cdk1, in vitro. Dephosphorylated at Ser-330 by CDC14A and CDC14B around early anaphase By similarity.

Acetylated by EP300; acetylation leads both to the decreased of SIRT2-mediated alpha-tubulin deacetylase activity and SIRT2-mediated down-regulation of TP53 transcriptional activity By similarity.

Ubiquitinated By similarity.

Miscellaneous

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

Sequence similarities

Belongs to the sirtuin family. Class I subfamily.

Contains 1 deacetylase sirtuin-type domain.

Ontologies

Keywords
   Biological processAutophagy
Cell cycle
Cell division
Differentiation
Meiosis
Mitosis
Neurogenesis
Transcription
Transcription regulation
   Cellular componentCell membrane
Cell projection
Chromosome
Cytoplasm
Cytoskeleton
Membrane
Microtubule
Nucleus
   LigandMetal-binding
NAD
Zinc
   Molecular functionHydrolase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processcellular lipid catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to epinephrine stimulus

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to hepatocyte growth factor stimulus

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to molecule of bacterial origin

Inferred from sequence or structural similarity. Source: UniProtKB

hepatocyte growth factor receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

histone H3 deacetylation

Inferred from sequence or structural similarity. Source: UniProtKB

histone H4 deacetylation

Inferred from sequence or structural similarity. Source: UniProtKB

mitotic nuclear division

Inferred from electronic annotation. Source: UniProtKB-KW

myelination in peripheral nervous system

Inferred from mutant phenotype Ref.5. Source: UniProtKB

negative regulation of cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of defense response to bacterium

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of fat cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of oligodendrocyte progenitor proliferation

Inferred from mutant phenotype Ref.4. Source: UniProtKB

negative regulation of peptidyl-threonine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of striated muscle tissue development

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-lysine deacetylation

Inferred from sequence or structural similarity. Source: UniProtKB

phosphatidylinositol 3-kinase signaling

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of attachment of spindle microtubules to kinetochore

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cell division

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of meiosis

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of oocyte maturation

Inferred from sequence or structural similarity. Source: UniProtKB

proteasome-mediated ubiquitin-dependent protein catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

protein deacetylation

Inferred from mutant phenotype Ref.5. Source: UniProtKB

protein kinase B signaling

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cell cycle

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of myelination

Inferred from mutant phenotype Ref.5. Source: UniProtKB

tubulin deacetylation

Inferred from direct assay Ref.4. Source: UniProtKB

   Cellular_componentSchmidt-Lanterman incisure

Inferred from direct assay Ref.5. Source: UniProtKB

centriole

Inferred from sequence or structural similarity. Source: UniProtKB

centrosome

Inferred from sequence or structural similarity. Source: UniProtKB

chromosome

Inferred from sequence or structural similarity. Source: UniProtKB

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

glial cell projection

Inferred from direct assay Ref.4. Source: UniProtKB

juxtaparanode region of axon

Inferred from direct assay Ref.4. Source: UniProtKB

lateral loop

Inferred from direct assay Ref.5. Source: UniProtKB

meiotic spindle

Inferred from sequence or structural similarity. Source: UniProtKB

microtubule

Inferred from electronic annotation. Source: UniProtKB-KW

midbody

Inferred from sequence or structural similarity. Source: UniProtKB

mitotic spindle

Inferred from sequence or structural similarity. Source: UniProtKB

myelin sheath

Inferred from direct assay Ref.4. Source: UniProtKB

nuclear heterochromatin

Inferred from direct assay Ref.4. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

paranodal junction

Inferred from direct assay Ref.5. Source: UniProtKB

paranode region of axon

Inferred from direct assay Ref.4. Source: UniProtKB

perikaryon

Inferred from direct assay Ref.4. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

spindle

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionNAD+ binding

Inferred from electronic annotation. Source: InterPro

NAD-dependent histone deacetylase activity (H4-K16 specific)

Inferred from sequence or structural similarity. Source: UniProtKB

NAD-dependent protein deacetylase activity

Inferred from direct assay Ref.4. Source: UniProtKB

chromatin binding

Inferred from sequence or structural similarity. Source: UniProtKB

histone deacetylase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein deacetylase activity

Inferred from sequence or structural similarity. Source: UniProtKB

tubulin deacetylase activity

Inferred from direct assay Ref.4. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 350350NAD-dependent protein deacetylase sirtuin-2
PRO_0000244536

Regions

Domain28 – 303276Deacetylase sirtuin-type
Nucleotide binding47 – 6721NAD By similarity
Nucleotide binding130 – 1334NAD By similarity
Nucleotide binding224 – 2263NAD By similarity
Nucleotide binding249 – 2513NAD By similarity
Region79 – 835Peptide inhibitor binding By similarity
Region195 – 26470Peptide inhibitor binding By similarity
Motif4 – 1411Nuclear export signal By similarity

Sites

Active site1501Proton acceptor By similarity
Metal binding1581Zinc By similarity
Metal binding1631Zinc By similarity
Metal binding1841Zinc By similarity
Metal binding1871Zinc By similarity
Binding site2871NAD; via amide nitrogen By similarity

Amino acid modifications

Modified residue3301Phosphoserine; by CDK2 (in a cyclin E-CDK2 complex); by CDK5 (in the cyclin p35-CDK5) By similarity
Modified residue3341Phosphoserine By similarity

Experimental info

Mutagenesis1311N → A: Reduced deacetylase activity on alpha-tubulin and stimulates oligodendrocyte precursor (OLP) differentiation. Ref.4
Mutagenesis1331D → A: Reduced deacetylase activity on alpha-tubulin. Ref.4
Mutagenesis1501H → A: Reduced deacetylase activity on alpha-tubulin and stimulates oligodendrocyte precursor (OLP) differentiation. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Q5RJQ4 [UniParc].

Last modified December 21, 2004. Version 1.
Checksum: EA3621A7CCE695FB

FASTA35039,319
        10         20         30         40         50         60 
MDFLRNLFTQ TLGLGSQKER LLDELTLEGV TRYMQSERCR RVICLVGAGI STSAGIPDFR 

        70         80         90        100        110        120 
SPSTGLYANL EKYHLPYPEA IFEISYFKKH PEPFFALAKE LYPGQFKPTI CHYFIRLLKE 

       130        140        150        160        170        180 
KGLLLRCYTQ NIDTLERVAG LEPQDLVEAH GTFYTSHCVN TSCGKEYTMS WMKEKIFSEA 

       190        200        210        220        230        240 
TPKCEKCQNV VKPDIVFFGE NLPPRFFSCM QSDFSKVDLL IIMGTSLQVQ PFASLISKAP 

       250        260        270        280        290        300 
LATPRLLINK EKTGQTDPFL GMMMGLGGGM DFDSKKAYRD VAWLGDCDQG CLALADLLGW 

       310        320        330        340        350 
KELEDLVRRE HANIDAQSGS QASNPSATVS PRKSPPPAKE AARTKEKEEH 

« Hide

References

« Hide 'large scale' references
[1]"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: Testis.
[2]Lubec G., Afjehi-Sadat L., Chen W.-Q., Kang S.U.
Submitted (JUL-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 6-18; 21-32; 41-116; 176-183; 187-216; 239-245; 302-308 AND 310-332, IDENTIFICATION BY MASS SPECTROMETRY.
Strain: Sprague-Dawley.
Tissue: Brain, Hippocampus and Spinal cord.
[3]"A novel seven transmembrane receptor induced during the early steps of astrocyte differentiation identified by differential expression."
De Smet C., Nishimori H., Furnari F.B., Boegler O., Huang H.-J.S., Cavenee W.K.
J. Neurochem. 81:575-588(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION.
[4]"Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating alpha-tubulin."
Li W., Zhang B., Tang J., Cao Q., Wu Y., Wu C., Guo J., Ling E.A., Liang F.
J. Neurosci. 27:2606-2616(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN DEACETYLATION OF ALPHA TUBULIN, FUNCTION AS REGULATOR OF OLIGODENDROCYTE DIFFERENTIATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, MUTAGENESIS OF ASN-131; ASP-133 AND HIS-150.
[5]"Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling."
Beirowski B., Gustin J., Armour S.M., Yamamoto H., Viader A., North B.J., Michan S., Baloh R.H., Golden J.P., Schmidt R.E., Sinclair D.A., Auwerx J., Milbrandt J.
Proc. Natl. Acad. Sci. U.S.A. 108:E952-961(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN REGULATION OF PERIPHERAL MYELINATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[6]"SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis."
Park S.H., Zhu Y., Ozden O., Kim H.S., Jiang H., Deng C.X., Gius D., Vassilopoulos A.
Transl. Cancer Res. 1:15-21(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW, FUNCTION AS A TUMOR SUPPRESSOR.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
BC086545 mRNA. Translation: AAH86545.1.
RefSeqNP_001008369.1. NM_001008368.1.
UniGeneRn.59887.

3D structure databases

ProteinModelPortalQ5RJQ4.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid262752. 1 interaction.
STRING10116.ENSRNOP00000027384.

PTM databases

PhosphoSiteQ5RJQ4.

Proteomic databases

PaxDbQ5RJQ4.
PRIDEQ5RJQ4.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000064153; ENSRNOP00000059450; ENSRNOG00000020102.
GeneID361532.
KEGGrno:361532.
UCSCRGD:621481. rat.

Organism-specific databases

CTD22933.
RGD621481. Sirt2.

Phylogenomic databases

eggNOGCOG0846.
GeneTreeENSGT00740000115546.
HOGENOMHOG000085952.
HOVERGENHBG057095.
InParanoidQ5RJQ4.
KOK11412.
OMATICHYFM.
OrthoDBEOG7WX09C.

Gene expression databases

GenevestigatorQ5RJQ4.

Family and domain databases

Gene3D3.40.50.1220. 2 hits.
InterProIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
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

NextBio676633.

Entry information

Entry nameSIR2_RAT
AccessionPrimary (citable) accession number: Q5RJQ4
Entry history
Integrated into UniProtKB/Swiss-Prot: June 27, 2006
Last sequence update: December 21, 2004
Last modified: July 9, 2014
This is version 83 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families