Biology:CTBP2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

C-terminal-binding protein 2 also known as CtBP2 is a protein that in humans is encoded by the CTBP2 gene.[1][2][3]

Function

The CtBPs - CtBP1 and CtBP2 in mammals - are among the best characterized transcriptional corepressors.[4] They typically turn their target genes off. They do this by binding to sequence-specific DNA-binding proteins that carry a short motif of the general form Proline-Isoleucine-Aspartate-Leucine-Serine (the PIDLS motif). They then recruit histone modifying enzymes, histone deacetylases, histone methylases and histone demethylases. These enzymes are thought to work together to remove activating and add repressive histone marks. For example, histone deacetylase 1 (HDAC1) and HDAC2 can remove the activating mark histone 3 acetyl lysine 9 (H3K9Ac), then the histone methylase G9a can add methyl groups, while the histone demethylase lysine specific demethylase 1 (LSD1) can remove the activating mark H3K4me.[5]

The CtBPs bind to many different DNA-binding proteins and also bind to co-repressors that are themselves bound to DNA-binding proteins, such as Friend of GATA (Fog).[6] CtBPs can also dimerize and multimerize to bridge larger transcriptional complexes. They appear to be primarily scaffold proteins that allow the assembly of gene repression complexes.

One interesting aspect of CtBPs is their ability to bind to NADH and to a lesser extent NAD+. It has been proposed that this will enable them to sense the metabolic status of the cell and to regulate genes in response to changes in the NADH/NAD+ ratio. Accordingly, CtBPs have been found to be important in fat biology, binding to key proteins such as PRDM16, NRIP, and FOG2.[7]

The full functional roles of CtBP proteins in mammals have been difficult to evaluate because of partial redundancy between CtBP1 and CtBP2.[8] Similarly, the early lethality of the CtBP2 knockout and of double knockout mice has precluded detailed analysis of the cellular effects of deleting these proteins. Important results have emerged from model organisms where there is only a single CtBP gene. In Drosophila CtBP is involved in development and in circadian rhythms.[9] In the worm C. elegans CtBP is involved in life span.[10] Both circadian rhythms and life span appear to be linked to metabolism supporting the role for CtBPs in metabolic sensing.

The mammalian CtBP2 gene produces alternative transcripts encoding two distinct proteins. In addition to the transcriptional repressor (corepressor) discussed above, there is a longer isoform that is a major component of specialized synapses known as synaptic ribbons. Both proteins contain a NAD+ binding domain similar to NAD+-dependent 2-hydroxyacid dehydrogenases. A portion of the 3'-untranslated region was used to map this gene to chromosome 21q21.3; however, it was noted that similar loci elsewhere in the genome are likely. Blast analysis shows that this gene is present on chromosome 10.[3]

Alternative Promoter Usage

In the vertebrate retina, the CtBP2 gene is transcribed from alternative promoters during retinal development yielding the CTBP2 transcriptional coregulator as well as the larger ribbon synapse scaffolding protein RIBEYE. [11] The multi use functionality of the CtBP2 locus appears to be conserved between avian and primate retinae with production of the RIBEYE mRNA being developmentally delayed by an epigenetic silencing mechanism. [12] In the developing human retina, transcription of the RIBEYE mRNA isoform is epigenetically regulated by DNA methylation. DNA sequences comprising the proximal RIBEYE promoter are enriched for DNA methylation and delay transcription of this isoform, possibly by inhibiting binding of the Cone-rod homeobox (CRX) transcription factor. [12] Global transcript analysis of human pluripotent stem cell (hPSC)-derived 3D retinal organoids demonstrates early and persistent expression of the CTPB2 isoform followed by delayed RIBEYE expression in the developing human eye. [13]

Interactions

CTBP2 has been shown to interact with:


References

  1. ↑ 1.0 1.1 "Cloning and characterization of mCtBP2, a co-repressor that associates with basic Krüppel-like factor and other mammalian transcriptional regulators". EMBO J. 17 (17): 5129–40. September 1998. doi:10.1093/emboj/17.17.5129. PMID 9724649. 
  2. ↑ Chinnadurai G (February 2002). "CtBP, an unconventional transcriptional corepressor in development and oncogenesis". Mol. Cell 9 (2): 213–24. doi:10.1016/S1097-2765(02)00443-4. PMID 11864595. 
  3. ↑ 3.0 3.1 "Entrez Gene: CTBP2 C-terminal binding protein 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1488. 
  4. ↑ "The CtBP family: enigmatic and enzymatic transcriptional co-repressors". BioEssays 23 (8): 683–90. August 2001. doi:10.1002/bies.1097. PMID 11494316. 
  5. ↑ "Histone demethylation mediated by the nuclear amine oxidase homolog LSD1". Cell 119 (7): 941–53. December 2004. doi:10.1016/j.cell.2004.12.012. PMID 15620353. 
  6. ↑ "Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers". EMBO J. 18 (10): 2812–22. May 1999. doi:10.1093/emboj/18.10.2812. PMID 10329627. 
  7. ↑ "C-terminal binding protein: A metabolic sensor implicated in regulating adipogenesis". Int. J. Biochem. Cell Biol. 43 (5): 693–6. May 2011. doi:10.1016/j.biocel.2011.01.017. PMID 21281737. 
  8. ↑ "Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development". Mol. Cell. Biol. 22 (15): 5296–307. August 2002. doi:10.1128/mcb.22.15.5296-5307.2002. PMID 12101226. 
  9. ↑ "C-terminal binding protein (CtBP) activates the expression of E-box clock genes with CLOCK/CYCLE in Drosophila". PLOS ONE 8 (4): e63113. 2013. doi:10.1371/journal.pone.0063113. PMID 23646183. Bibcode: 2013PLoSO...863113I. 
  10. ↑ "The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span". Proc. Natl. Acad. Sci. U.S.A. 106 (5): 1496–501. February 2009. doi:10.1073/pnas.0802674106. PMID 19164523. Bibcode: 2009PNAS..106.1496C. 
  11. ↑ "RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function". Neuron 28 (3): 857–872. 2000. doi:10.1016/s0896-6273(00)00159-8. PMID 11163272. 
  12. ↑ 12.0 12.1 "Temporal and isoform-specific expression of CTBP2 is evolutionarily conserved between the developing chick and human retina". Front. Mol. Neurosci. 14: 773356. January 2022. doi:10.3389/fnmol.2021.773356. PMID 35095414. 
  13. ↑ "Bulk RNA sequencing analysis of developing human induced pluripotent stem cell-derived retinal organoids". Sci. Data 9 (1): 759. December 2022. doi:10.1038/s41597-022-01853-x. PMID 36494376. 
  14. ↑ 14.0 14.1 "The LIM protein FHL3 binds basic Krüppel-like factor/Krüppel-like factor 3 and its co-repressor C-terminal-binding protein 2". J. Biol. Chem. 278 (15): 12786–95. 2003. doi:10.1074/jbc.M300587200. PMID 12556451. 
  15. ↑ "Human Krüppel-like factor 8: a CACCC-box binding protein that associates with CtBP and represses transcription". Nucleic Acids Res. 28 (9): 1955–62. 2000. doi:10.1093/nar/28.9.1955. PMID 10756197. 
  16. ↑ "Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription". Curr. Biol. 13 (14): 1234–9. 2003. doi:10.1016/S0960-9822(03)00454-8. PMID 12867035. https://eprints.soton.ac.uk/26486/1/AHM2003_postprint.pdf. 
  17. ↑ "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
  18. ↑ "Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition". Nucleic Acids Res. 32 (6): 1957–66. 2004. doi:10.1093/nar/gkh524. PMID 15060175. 
  19. ↑ "SOX6 binds CtBP2 to repress transcription from the Fgf-3 promoter". Nucleic Acids Res. 29 (16): 3347–55. 2001. doi:10.1093/nar/29.16.3347. PMID 11504872. 
  20. ↑ "hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation". J. Biol. Chem. 274 (33): 23491–8. 1999. doi:10.1074/jbc.274.33.23491. PMID 10438528. 

Further reading

External links



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