Q5RJQ4 (SIR2_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 83. History...
Names and origin
|Protein names||Recommended name:|
NAD-dependent protein deacetylase sirtuin-2
Regulatory protein SIR2 homolog 2
SIR2-like protein 2
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||350 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein.
Binds 1 zinc ion per subunit By similarity.
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.
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.
Nucleus By similarity. Cytoplasm. Cytoplasm › perinuclear region. Perikaryon. Myelin membrane. Cell projection. Cytoplasm › cytoskeleton. Cell projection › growth cone By similarity. Myelin membrane By similarity. Cytoplasm › cytoskeleton › microtubule organizing center › centrosome By similarity. Cytoplasm › cytoskeleton › spindle By similarity. Chromosome By similarity. Cytoplasm › cytoskeleton › microtubule organizing center › centrosome › centriole 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
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
In oligodendrocytes during differentiation of CG-4 cells. Ref.3
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.
Has some ability to deacetylate histones in vitro, but seeing its subcellular location, this is unlikely in vivo By similarity.
Contains 1 deacetylase sirtuin-type domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 350||350||NAD-dependent protein deacetylase sirtuin-2||PRO_0000244536|
|Domain||28 – 303||276||Deacetylase sirtuin-type|
|Nucleotide binding||47 – 67||21||NAD By similarity|
|Nucleotide binding||130 – 133||4||NAD By similarity|
|Nucleotide binding||224 – 226||3||NAD By similarity|
|Nucleotide binding||249 – 251||3||NAD By similarity|
|Region||79 – 83||5||Peptide inhibitor binding By similarity|
|Region||195 – 264||70||Peptide inhibitor binding By similarity|
|Motif||4 – 14||11||Nuclear export signal By similarity|
|Active site||150||1||Proton acceptor By similarity|
|Metal binding||158||1||Zinc By similarity|
|Metal binding||163||1||Zinc By similarity|
|Metal binding||184||1||Zinc By similarity|
|Metal binding||187||1||Zinc By similarity|
|Binding site||287||1||NAD; via amide nitrogen By similarity|
Amino acid modifications
|Modified residue||330||1||Phosphoserine; by CDK2 (in a cyclin E-CDK2 complex); by CDK5 (in the cyclin p35-CDK5) By similarity|
|Modified residue||334||1||Phosphoserine By similarity|
|Mutagenesis||131||1||N → A: Reduced deacetylase activity on alpha-tubulin and stimulates oligodendrocyte precursor (OLP) differentiation. Ref.4|
|Mutagenesis||133||1||D → A: Reduced deacetylase activity on alpha-tubulin. Ref.4|
|Mutagenesis||150||1||H → A: Reduced deacetylase activity on alpha-tubulin and stimulates oligodendrocyte precursor (OLP) differentiation. Ref.4|
|||"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].
|||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.
Tissue: Brain, Hippocampus and Spinal cord.
|||"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.
|||"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.
|||"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.
|||"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.|
|BC086545 mRNA. Translation: AAH86545.1.|
|RefSeq||NP_001008369.1. NM_001008368.1. |
3D structure databases
Protein-protein interaction databases
|BioGrid||262752. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000064153; ENSRNOP00000059450; ENSRNOG00000020102. |
|UCSC||RGD:621481. rat. |
|RGD||621481. Sirt2. |
Gene expression databases
Family and domain databases
|Gene3D||220.127.116.110. 2 hits. |
|InterPro||IPR029035. DHS-like_NAD/FAD-binding_dom. |
|PANTHER||PTHR11085. PTHR11085. 1 hit. |
|Pfam||PF02146. SIR2. 1 hit. |
|PIRSF||PIRSF037938. SIR2_euk. 1 hit. |
|SUPFAM||SSF52467. SSF52467. 1 hit. |
|PROSITE||PS50305. SIRTUIN. 1 hit. |
|Accession||Primary (citable) accession number: Q5RJQ4|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families