TRANSCRIPTION COREGULATOR

In the field of molecular biology, 'transcription coregulators' are proteins that interact with transcription factors to either activate or repress the transcription of specific genes.^[1] Transcription coregulators which 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 either more or less accessible to transcription. One major class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.^[2]

Contents

Histone acyltransferases

Nuclear receptor coactivators

Nuclear receptor corepressors

Dual function activator/repressors

ATP-dependent remodeling factors

See also

References

External links

Histone acyltransferases

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. Conversely 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 acylate 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.
Conversely, many corepressor possess the ability to recruit histone deacetylase (HDAC) enzymes to promoters. These enzymes catalyze the hydrolysis of acylated lysine residues restoring the positive charge to histone proteins and hence the tight association between histone and DNA. For example, PELP-1 can act as a transcriptional corepressor for transcription factors in the nuclear receptor family such as glucocorticoid receptors.^[3]

Nuclear receptor coactivators

Nuclear receptors bind to coactivators in a ligand dependent manor. 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 grove on the surface of ligand binding domain of nuclear receptors.^[4] Examples include:

★ NCOA1 (nuclear receptor coactivator 1)/SRC-1 (steroid receptor coactivator-1)/

★ NCOA2 (nuclear receptor coactivator 2)/GRIP1 (glucocorticoid receptor interacting protein 1)

★ NCOA3 (nuclear receptor coactivator 3)/AIB1 (amplified in breast)

★ NCOA4 (nuclear receptor coactivator 4)/ARA70 (androgen receptor associated protein 70)

★ NCOA5 (nuclear receptor coactivator 5)

★ NCOA6 (nuclear receptor coactivator 6)

★ NCOA7 (nuclear receptor coactivator 7)

★ PGC1 (proliferator activated receptor gamma coactivator 1) ,

★ CBP (cAMP response element-binding (CREB) protein-binding protein)
★ p300

★ PCAF (p300/CBP associating factor) ^[5]

★ ARA54 (androgen receptor associated protein 54)

★ ARA55 (androgen receptor associated protein 55)

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).^[6] In addition, copressors bind preferentially to the apo (ligand free) form of the nuclear receptor (or possibly antagonist bound receptor).

★ NCOR1 (Nuclear receptor CO-Repressor) ()

★ NCOR2 (Nuclear receptor CO-Repressor) ()/SMRT (Silencing Mediator (co-repressor) for Retinoid and Thyroid-hormone receptors) (associates with histone deacetylase-3³)

★ LCoR (ligand-dependent corepressor) ()

★ RCOR (REST corepressor) (, , )

★ CtBP 602618 (associates with class II histone deacetylases)

★ Rb (retinoblastoma protein) (associates with histone deacetylase-1 and -2)

★ Sin3 ,

Dual function activator/repressors

★ PELP-1 (proline, glutamic acid and leucine rich protein 1)

★ NSD1

★ RIP14 (RXR-interacting protein 14) ³

ATP-dependent remodeling factors

★ SWI/SNF family

★ chromatin structure remodeling complex

★ ISWI protein ,

See also

★ Coactivator (genetics)

★ Corepressor (genetics)

★ RNA polymerase control by chromatin structure

★ Transcription

★ Transcription factor

References

1. The coregulator exchange in transcriptional functions of nuclear receptors, Glass CK, Rosenfeld MG, , , Genes Dev, 2000
2. ATP-dependent remodeling and acetylation as regulators of chromatin fluidity, Kingston RE, Narlikar GJ, , , Genes Dev, 1999
3. The transcriptional corepressor, PELP1, recruits HDAC2 and masks histones using two separate domains, Choi YB, Ko JK, Shin J, , , J Biol Chem, 2004
4. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen, Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL, , , Cell, 1998
5. Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha, Vadlamudi RK, Wang RA, Mazumdar A, Kim Y, Shin J, Sahin A, Kumar R, , , J Biol Chem, 2001
6. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha, Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT, Parks DJ, Moore JT, Kliewer SA, Willson TM, Stimmel JB, , , Nature, 2002

External links

★ Nuclear Receptor Signalling Atlas (NIH-funded research consortium and database; includes open-access PubMed-indexed journal, Nuclear Receptor Signaling)