NAD-dependent protein deacetylase sirtuin-2 (SIRT2)
The protein contains 389 amino acids for an estimated molecular weight of 43182 Da.
NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors (PubMed:24177535, PubMed:12620231, PubMed:16648462, PubMed:18249187, PubMed:18332217, PubMed:18995842, PubMed:20587414, PubMed:21081649, PubMed:20543840, PubMed:22014574, PubMed:21726808, PubMed:21949390, PubMed:22771473, PubMed:23468428, PubMed:23908241, PubMed:24940000, PubMed:24769394, PubMed:24681946). 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 both with 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 depo (updated: Jan. 31, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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Biological Process
Autophagy
Cell division
Cellular lipid catabolic process
Cellular response to caloric restriction
Cellular response to epinephrine stimulus
Cellular response to hepatocyte growth factor stimulus
Cellular response to hypoxia
Cellular response to molecule of bacterial origin
Cellular response to oxidative stress
Chromatin silencing
Chromatin silencing at telomere
Gene silencing
Hepatocyte growth factor receptor signaling pathway
Histone deacetylation
Histone H3 deacetylation
Histone H4 deacetylation
Innate immune response
Meiotic cell cycle
Mitotic nuclear division
Mitotic nuclear membrane reassembly
Myelination in peripheral nervous system
Negative regulation of autophagy
Negative regulation of cell population proliferation
Negative regulation of defense response to bacterium
Negative regulation of fat cell differentiation
Negative regulation of NLRP3 inflammasome complex assembly
Negative regulation of oligodendrocyte progenitor proliferation
Negative regulation of peptidyl-threonine phosphorylation
Negative regulation of protein catabolic process
Negative regulation of reactive oxygen species metabolic process
Negative regulation of striated muscle tissue development
Negative regulation of transcription by RNA polymerase II
Negative regulation of transcription from RNA polymerase II promoter in response to hypoxia
Negative regulation of transcription, DNA-templated
Peptidyl-lysine deacetylation
Phosphatidylinositol 3-kinase signaling
Positive regulation of attachment of spindle microtubules to kinetochore
Positive regulation of cell division
Positive regulation of DNA binding
Positive regulation of execution phase of apoptosis
Positive regulation of meiotic nuclear division
Positive regulation of oocyte maturation
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process involved in cellular response to hypoxia
Positive regulation of transcription by RNA polymerase II
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein ADP-ribosylation
Protein deacetylation
Protein kinase B signaling
RDNA heterochromatin assembly
Regulation of cell cycle
Regulation of exit from mitosis
Regulation of myelination
Regulation of phosphorylation
Response to redox state
Ripoptosome assembly involved in necroptotic process
Substantia nigra development
Transcription, DNA-templated
Tubulin deacetylation
Cellular Component
Centriole
Centrosome
Chromatin silencing complex
Chromosome
Chromosome, telomeric region
Cytoplasm
Cytosol
Glial cell projection
Growth cone
Heterochromatin
Juxtaparanode region of axon
Lateral loop
Meiotic spindle
Microtubule
Midbody
Mitochondrion
Mitotic spindle
Myelin sheath
Nuclear heterochromatin
Nucleolus
Nucleus
Paranodal junction
Paranode region of axon
Perikaryon
Perinuclear region of cytoplasm
Plasma membrane
Schmidt-Lanterman incisure
Spindle
Molecular Function
Chromatin binding
Histone acetyltransferase binding
Histone deacetylase activity
Histone deacetylase binding
NAD+ ADP-ribosyltransferase activity
NAD+ binding
NAD-dependent histone deacetylase activity
NAD-dependent histone deacetylase activity (H4-K16 specific)
NAD-dependent protein deacetylase activity
Protein deacetylase activity
Transcription factor binding
Tubulin deacetylase activity
Ubiquitin binding
Zinc ion binding
The reference OMIM entry for this protein is 604480
Sirtuin 2; sirt2
Sir2, s. cerevisiae, homolog-like 2; sir2l2
Sir2l
DESCRIPTION
SIRT2 is an NAD-dependent deacetylase that mediates deacetylation of alpha-tubulin (see 602529). During the cell cycle, SIRT2 regulates mitotic structures, including the centrosome, mitotic spindle, and midbody. SIRT2 may also regulate centrosome amplification and ciliogenesis (summary by Zhou et al., 2014).CLONING
The yeast Sir2 (silent information regulator-2) protein (Shore et al., 1984) regulates epigenetic gene silencing and, as a possible antiaging effect, suppresses recombination of rDNA. Studies involving cobB, a bacterial Sir2-like gene, have suggested that Sir2 may encode a pyridine nucleotide transferase. By in silico and PCR-cloning techniques, Frye (1999) obtained cDNA sequences encoding 5 human Sir2-like genes, which they called sirtuin-1 to -5 (SIRT1 to SIRT5). The SIRT1 (604479) sequence has the closest homology to the S. cerevisiae Sir2 protein, while SIRT4 (604482) and SIRT5 (604483) more closely resemble prokaryotic sirtuin sequences. PCR analysis showed that the 5 human sirtuins are widely expressed in fetal and adult tissues. Afshar and Murnane (1999) sequenced a full-length SIRT2 (SIR2L) EST clone. The deduced 352-amino acid protein has a calculated molecular mass of 39.5 kD. It has 2 potential leucine zipper motifs, 6 possible N-myristoylation sites, and several potential protein kinase C (see PRKCA, 176960) phosphorylation sites. Northern blot analysis detected variable expression of a 2.1-kb transcript in all tissues examined, with higher expression in heart, brain, and skeletal muscle, and lower expression in placenta and lung. Fluorescence-tagged SIRT2 localized primarily in the cytoplasm of transfected human fibroblasts and a tumor cell line.GENE FUNCTION
Frye (1999) found that recombinant human SIRT2 was able to cause radioactivity to be transferred from (32P)NAD to bovine serum albumin (BSA). When a conserved histidine within SIRT2 was converted to tyrosine, the mutant recombinant protein was unable to transfer radioactivity from (32P)NAD to BSA. These results suggested that the sirtuins may function via mono-ADP-ribosylation of proteins. Tanny et al. (1999) showed that the yeast Sir2 protein can transfer labeled phosphate from nicotinamide adenine dinucleotide to itself and histones in vitro. A modified form of Sir2, which results from its automodification activity, was specifically recognized by anti-mono-ADP-ribose antibodies, suggesting that Sir2 is an ADP-ribosyltransferase. Mutation of a phylogenetically invariant histidine (his364 to tyr) in Sir2 abolished both its enzymatic activity in vitro and its silencing functions in vivo. However, the mutant protein was associated with chromatin and other silencing factors in a manner similar to wildtype Sir2. These findings suggested that Sir2 contains an ADP-ribosyltransferase activity that is essential for its silencing function. Rogina et al. (2002) found that under 2 life-extending conditions, Rpd3 (601241) mutants fed normal food and wildtype flies fed low calorie food, Sir2 expression was increased 2-fold. Carbonylated proteins, which are a sign of irreversible oxidative damage, were visualized in single cells of S. cerevisiae, revealing that they accumulate with replicative age. Aguilaniu et al. (2003) showed the carbonylated proteins were not inherited by daughter cells during cytokinesis. Mother cells of a yeast strain lacking the Sir2 gene, a life-span determinant, failed to retain oxidatively damaged p ... More on the omim web site
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 604480 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed