|C-terminal binding protein 2|
PDB rendering based on 2ome.
The CtBPs - CtBP1 and CtBP2 in mammals - are among the best characterized transcriptional corepressors. 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.
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). 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.
The full functional roles of CtBP proteins in mammals have been difficult to evaluate because of partial redundancy between CtBP1 and CtBP2. 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. In the worm C. elegans CtBP is involved in life span. 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.
CTBP2 has been shown to interact with:
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- 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.
- "Entrez Gene: CTBP2 C-terminal binding protein 2".
- Turner J, Crossley M (August 2001). "The CtBP family: enigmatic and enzymatic transcriptional co-repressors". BioEssays 23 (8): 683–90. doi:10.1002/bies.1097. PMID 11494316.
- Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (December 2004). "Histone demethylation mediated by the nuclear amine oxidase homolog LSD1". Cell 119 (7): 941–53. doi:10.1016/j.cell.2004.12.012. PMID 15620353.
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- Jack BH, Pearson RC, Crossley M (May 2011). "C-terminal binding protein: A metabolic sensor implicated in regulating adipogenesis". Int. J. Biochem. Cell Biol. 43 (5): 693–6. doi:10.1016/j.biocel.2011.01.017. PMID 21281737.
- Hildebrand JD, Soriano P (August 2002). "Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development". Mol. Cell. Biol. 22 (15): 5296–307. doi:10.1128/mcb.22.15.5296-5307.2002. PMC 133942. PMID 12101226.
- Itoh TQ, Matsumoto A, Tanimura T (2013). "C-terminal binding protein (CtBP) activates the expression of E-box clock genes with CLOCK/CYCLE in Drosophila". PLoS ONE 8 (4): e63113. doi:10.1371/journal.pone.0063113. PMC 3640014. PMID 23646183.
- Chen S, Whetstine JR, Ghosh S, Hanover JA, Gali RR, Grosu P, Shi Y (February 2009). "The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span". Proc. Natl. Acad. Sci. U.S.A. 106 (5): 1496–501. doi:10.1073/pnas.0802674106. PMC 2635826. PMID 19164523.
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- van Vliet J, Turner J, Crossley M (2000). "Human Krüppel-like factor 8: a CACCC-box binding protein that associates with CtBP and represses transcription". Nucleic Acids Res. 28 (9): 1955–62. doi:10.1093/nar/28.9.1955. PMC 103308. PMID 10756197.
- Mirnezami AH, Campbell SJ, Darley M, Primrose JN, Johnson PW, Blaydes JP (2003). "Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription". Curr. Biol. 13 (14): 1234–9. doi:10.1016/S0960-9822(03)00454-8. PMID 12867035.
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- Castet A, Boulahtouf A, Versini G, Bonnet S, Augereau P, Vignon F, Khochbin S, Jalaguier S, Cavaillès V (2004). "Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition". Nucleic Acids Res. 32 (6): 1957–66. doi:10.1093/nar/gkh524. PMC 390375. PMID 15060175.
- Murakami A, Ishida S, Thurlow J, Revest JM, Dickson C (2001). "SOX6 binds CtBP2 to repress transcription from the Fgf-3 promoter". Nucleic Acids Res. 29 (16): 3347–55. doi:10.1093/nar/29.16.3347. PMC 55854. PMID 11504872.
- Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B (1999). "hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation". J. Biol. Chem. 274 (33): 23491–8. doi:10.1074/jbc.274.33.23491. PMID 10438528.
- Schaeper U, Boyd JM, Verma S, Uhlmann E, Subramanian T, Chinnadurai G (November 1995). "Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation". Proc. Natl. Acad. Sci. U.S.A. 92 (23): 10467–71. doi:10.1073/pnas.92.23.10467. PMC 40632. PMID 7479821.
- Sewalt RG, Gunster MJ, van der Vlag J, Satijn DP, Otte AP (January 1999). "C-Terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate Polycomb proteins". Mol. Cell. Biol. 19 (1): 777–87. PMC 83934. PMID 9858600.
- Furusawa T, Moribe H, Kondoh H, Higashi Y (December 1999). "Identification of CtBP1 and CtBP2 as corepressors of zinc finger-homeodomain factor deltaEF1". Mol. Cell. Biol. 19 (12): 8581–90. PMC 84984. PMID 10567582.
- Yu X, Baer R (June 2000). "Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor". J. Biol. Chem. 275 (24): 18541–9. doi:10.1074/jbc.M909494199. PMID 10764811.
- Schmitz F, Königstorfer A, Südhof TC (December 2000). "RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function". Neuron 28 (3): 857–72. doi:10.1016/S0896-6273(00)00159-8. PMID 11163272.
- Valenta T, Lukas J, Korinek V (May 2003). "HMG box transcription factor TCF-4's interaction with CtBP1 controls the expression of the Wnt target Axin2/Conductin in human embryonic kidney cells". Nucleic Acids Res. 31 (9): 2369–80. doi:10.1093/nar/gkg346. PMC 154232. PMID 12711682.
- Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (June 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nat. Biotechnol. 22 (6): 707–16. doi:10.1038/nbt971. PMID 15146197.
- Alpatov R, Munguba GC, Caton P, Joo JH, Shi Y, Shi Y, Hunt ME, Sugrue SP (December 2004). "Nuclear speckle-associated protein Pnn/DRS binds to the transcriptional corepressor CtBP and relieves CtBP-mediated repression of the E-cadherin gene". Mol. Cell. Biol. 24 (23): 10223–35. doi:10.1128/MCB.24.23.10223-10235.2004. PMC 529029. PMID 15542832.