C-terminal-binding protein 2 also known as CtBP2 is a protein that in humans is encoded by the CTBP2 gene. [5] [6] [7]
C-terminal-binding protein 2 also known as CtBP2 is a protein that in humans is encoded by the CTBP2 gene. [5] [6] [7]
The CtBPs - CtBP1 and CtBP2 in mammals - are among the best characterized transcriptional corepressors. [8] 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. [9]
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). [10] 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. [11]
The full functional roles of CtBP proteins in mammals have been difficult to evaluate because of partial redundancy between CtBP1 and CtBP2. [12] 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. [13] In the worm C. elegans CtBP is involved in life span. [14] 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. [7]
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. [15] 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. [16] 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. [16] 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. [17]
CTBP2 has been shown to interact with:
In molecular genetics, the Krüppel-like family of transcription factors (KLFs) are a set of eukaryotic C2H2 zinc finger DNA-binding proteins that regulate gene expression. This family has been expanded to also include the Sp transcription factor and related proteins, forming the Sp/KLF family.
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that repress are known as corepressors. The mechanism of action of transcription coregulators is to modify chromatin structure and thereby make the associated DNA more or less accessible to transcription. In humans several dozen to several hundred coregulators are known, depending on the level of confidence with which the characterisation of a protein as a coregulator can be made. One class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the NCOR1 gene.
In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, but instead indirectly regulates gene expression by binding to repressors.
Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.
Zinc finger and BTB domain-containing protein 16 is a protein that in humans is encoded by the ZBTB16 gene.
Histone deacetylase 4, also known as HDAC4, is a protein that in humans is encoded by the HDAC4 gene.
C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the CTBP1 gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2.
Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.
Zinc finger E-box-binding homeobox 1 is a protein that in humans is encoded by the ZEB1 gene.
MDS1 and EVI1 complex locus protein EVI1 (MECOM) also known as ecotropic virus integration site 1 protein homolog (EVI-1) or positive regulatory domain zinc finger protein 3 (PRDM3) is a protein that in humans is encoded by the MECOM gene. EVI1 was first identified as a common retroviral integration site in AKXD murine myeloid tumors. It has since been identified in a plethora of other organisms, and seems to play a relatively conserved developmental role in embryogenesis. EVI1 is a nuclear transcription factor involved in many signaling pathways for both coexpression and coactivation of cell cycle genes.
DNA methyltransferase 1-associated protein 1 is an enzyme that in humans is encoded by the DMAP1 gene.
Retinoblastoma-binding protein 8 is a protein that in humans is encoded by the RBBP8 gene.
Krueppel-like factor 12 is a protein that in humans is encoded by the KLF12 gene.
Zinc finger protein ZFPM2, i.e. zinc finger protein, FOG family member 2, but also termed Friend of GATA2, Friend of GATA-2, FOG2, or FOG-2, is a protein that in humans is encoded by the ZFPM2 and in mice by the Zfpm2 gene.
Krueppel-like factor 8 is a protein that in humans is encoded by the KLF8 gene. KLF8 belongs to the family of KLF protein. KLF8 is activated by KLF1 along with KLF3 while KLF3 represses KLF8.
Zinc finger protein 366, also known as DC-SCRIPT, is a protein that in humans is encoded by the ZNF366 gene. The ZNF366 gene was first identified in a DNA comparison study between 85 kb of Fugu rubripes sequence containing 17 genes with its homologous loci in the human draft genome.
Krüppel-like factor 3 is a protein that in humans is encoded by the KLF3 gene.
Merlin Crossley, is an Australian molecular biologist, university teacher and administrator. In 2016, he was appointed as Deputy Vice-Chancellor (Academic) at the University of New South Wales.
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