Biology:Transcription coregulator

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Short description: Proteins that help regulate transcription

In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes.[1] 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.[2] One class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.[3]

Histone acetyltransferases

Nuclear DNA is normally tightly wrapped around histones rendering the DNA inaccessible to the general transcription machinery and hence this tight association prevents transcription of DNA. At physiological pH, the phosphate component of the DNA backbone is deprotonated which gives DNA a net negative charge. Histones are rich in lysine residues which at physiological pH are protonated and therefore positively charged. The electrostatic attraction between these opposite charges is largely responsible for the tight binding of DNA to histones.

Many coactivator proteins have intrinsic histone acetyltransferase (HAT) catalytic activity or recruit other proteins with this activity to promoters. These HAT proteins are able to acetylate the amine group in the sidechain of histone lysine residues which makes lysine much less basic, not protonated at physiological pH, and therefore neutralizes the positive charges in the histone proteins. This charge neutralization weakens the binding of DNA to histones causing the DNA to unwind from the histone proteins and thereby significantly increases the rate of transcription of this DNA.

Many corepressors can recruit histone deacetylase (HDAC) enzymes to promoters. These enzymes catalyze the hydrolysis of acetylated lysine residues restoring the positive charge to histone proteins and hence the tie between histone and DNA. PELP-1 can act as a transcriptional corepressor for transcription factors in the nuclear receptor family such as glucocorticoid receptors.[4]

Nuclear receptor coactivators

Nuclear receptors bind to coactivators in a ligand-dependent manner. A common feature of nuclear receptor coactivators is that they contain one or more LXXLL binding motifs (a contiguous sequence of 5 amino acids where L = leucine and X = any amino acid) referred to as NR (nuclear receptor) boxes. The LXXLL binding motifs have been shown by X-ray crystallography to bind to a groove on the surface of ligand binding domain of nuclear receptors.[5] Examples include:

Nuclear receptor corepressors

Corepressor proteins also bind to the surface of the ligand binding domain of nuclear receptors, but through a LXXXIXXX(I/L) motif of amino acids (where L = leucine, I = isoleucine and X = any amino acid).[7] In addition, compressors bind preferentially to the apo (ligand free) form of the nuclear receptor (or possibly antagonist bound receptor).

  • CtBP 602618 SIN3A (associates with class II histone deacetylases)
  • LCoR (ligand-dependent corepressor)
  • Nuclear receptor CO-Repressor (NCOR)
    • NCOR1 (NCOR1)
    • NCOR2 (NCOR2)/SMRT (Silencing Mediator (co-repressor) for Retinoid and Thyroid-hormone receptors) (associates with histone deacetylase-3[4])
  • Rb (retinoblastoma protein) RB1 (associates with histone deacetylase-1 and -2)
  • RCOR (REST corepressor)
  • Sin3
  • TIF1 (transcriptional intermediary factor 1)

Dual function activator/repressors

ATP-dependent remodeling factors

  • SWI/SNF family
  • chromatin structure remodeling complex
  • ISWI protein SMARCA1, SMARCA2

See also

References

  1. ↑ "The coregulator exchange in transcriptional functions of nuclear receptors". Genes Dev 14 (2): 121–41. 2000. doi:10.1101/gad.14.2.121. PMID 10652267. 
  2. ↑ "TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins". Nucleic Acids Res. 39 (Database issue): D106-10. Jan 2011. doi:10.1093/nar/gkq945. PMID 20965969. 
  3. ↑ "ATP-dependent remodeling and acetylation as regulators of chromatin fluidity". Genes Dev 13 (18): 2339–52. 1999. doi:10.1101/gad.13.18.2339. PMID 10500090. 
  4. ↑ 4.0 4.1 "The transcriptional corepressor, PELP1, recruits HDAC2 and masks histones using two separate domains". J Biol Chem 279 (49): 50930–41. 2004. doi:10.1074/jbc.M406831200. PMID 15456770. 
  5. ↑ "The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen". Cell 95 (7): 927–37. 1998. doi:10.1016/S0092-8674(00)81717-1. PMID 9875847. 
  6. ↑ "Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha". J Biol Chem 276 (41): 38272–9. 2001. doi:10.1074/jbc.M103783200. PMID 11481323. 
  7. ↑ "Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha". Nature 415 (6873): 813–7. 2002. doi:10.1038/415813a. PMID 11845213. Bibcode: 2002Natur.415..813X. 

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