Corepressor is a substance that inhibits gene expression. In prokaryotes, the secondary repressor is a small molecule, while in eukaryotes, the secondary repressor is a protein. The co-repressor does not bind directly to DNA, but indirectly regulates gene expression by binding to a repressor. The helper repressor downregulates gene expression by binding to and activating a repressor transcription factor. The repressor, in turn, binds to the gene's operator sequence, thereby blocking transcription of the gene.
In prokaryotes, the term co-repressor is used to denote an activating ligand for a repressor protein. For example, the E. coli tryptophan repressor (TrpR) is only capable of binding DNA and inhibits transcription of the trp operon when its co-repressor tryptophan binds thereto. In the absence of tryptophan, TrpR is called an aporepressor and is inactive in inhibiting gene transcription. The Trp operon encodes an enzyme responsible for the synthesis of tryptophan. Thus, TrpR provides a negative feedback mechanism that regulates tryptophan biosynthesis. In eukaryotes, a co-repressor is a protein that binds to a transcription factor. In the absence of a co-repressor and the presence of coactivators, transcription factors up-regulate gene expression. Coactivators and co-repressors compete for the same binding site on the transcription factor. The second mechanism by which a co-repressor can inhibit transcription initiation when bound to a transcription factor/DNA complex is through the recruitment of histone deacetylase, which catalyzes the removal of acetyl groups from lysine residues. This increases the positive charge on histones, which enhances the electrostatic attraction between positively charged histones and negatively charged DNA, making DNA difficult to transcribe.
Transcriptional Co-Repressors Proteins
Transcription co-regulators are proteins that interact with transcription factors to activate or inhibit the transcription of a particular gene. Transcriptional co-regulators that activate gene transcription are called coactivators, and inhibitors are called co-suppressors. The mechanism of action of transcriptional co-regulators is to modify the chromatin structure, thereby making the associated DNA more or less susceptible to transcription. Tens to hundreds of co-regulatory factors are known in humans, depending on the level of confidence that proteins can be characterized as co-regulators. A class of transcriptional co-regulators modify the chromatin structure by covalently modifying histones. The second ATP dependent class modifies the chromatin conformation.
Nuclear receptor corepressors
The Corepressor protein also binds to the surface of the ligand-binding domain of the nuclear receptor, but through the LXXXIXXX(I/L) motif of the amino acid (where L = leucine, I = isoleucine, X = any amino acid). In addition, the compressor preferentially binds to the apo (no ligand) form of the nuclear receptor (or may be an antagonist binding receptor).
The protein encoded by this gene is a transcriptional regulatory protein. It contains a paired amphipathic helix (PAH) domain, which is important for protein-protein interactions and may mediate inhibition by the Mad-Max complex.
Figure 1. Structure of the SIN3A protein.
Figure 2. Figure 1. Structure of the SIN3B protein.
LCOR is a transcriptional co-repressor widely expressed in fetal and adult tissues, recruited by a single LxxLL motif to an agonist-bound nuclear receptor, also known as the nuclear receptor (NR) cassette.
Figure 3. Structure of the LCOR protein.
Nuclear receptor CO-Repressor (NCOR)
NCOR1 is a transcriptional co-regulatory protein that contains several nuclear receptor interaction domains. In addition, NCOR1 appears to recruit histone deacetylases to the DNA promoter region. Therefore, NCOR1 assists nuclear receptors in down-regulating gene expression.
Figure 4. Structure of protein NCOR1.
NCOR2 is a transcriptional co-regulatory protein that contains several nuclear receptor interaction domains. In addition, NCOR2 appears to recruit histone deacetylases to the DNA promoter region. Therefore, NCOR2 assists nuclear receptors in down-regulating target gene expression.
Figure 5. Structure of the NCOR2 protein.
1. Pennacchio LA.; et al. Enhancers: five essential questions. Nature Reviews Genetics, 2016, 17(5):401-410.
2. Spiegelman BM.; et al. Biological control through regulated transcriptional coactivators. Nature Reviews Genetics. Cell. 2004,119 (2): 157-67.