- Source: Transcription coregulator
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 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.
= 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. Examples include:
ARA (androgen receptor associated protein)
ARA54 (RNF14)
ARA55 (TGFB1I1)
ARA70 (NCOA4)
AIRE
BCAS3 (breast carcinoma amplified sequence 3)
CREB-binding protein
CRTC (CREB regulated transcription coactivator)
CRTC1 (CRTC1)
CRTC2 (CRTC2)
CRTC3 (CRTC3)
CARM1 (coactivator-associated arginine methyltransferase 1) CARM1
Nuclear receptor coactivator (NCOA)
NCOA1/SRC-1 (steroid receptor coactivator-1)/ NCOA1
NCOA2/GRIP1 (glucocorticoid receptor interacting protein 1)/ TIF2 (transcriptional intermediary factor 2) NCOA2
NCOA3/AIB1 (amplified in breast) NCOA3
NCOA4/ARA70 (androgen receptor associated protein 70) NCOA4
NCOA5 (NCOA5)
NCOA6 (NCOA6)
NCOA7 (NCOA7)
p300 EP300
PCAF (p300/CBP associating factor) PCAF
PGC1 (proliferator activated receptor gamma coactivator 1)
PPARGC1A (PPARGC1A)
PPARGC1B (PPARGC1B)
PNRC (proline-rich nuclear receptor coactivator 1)
PNRC1 (PNRC1)
PNRC2 (PNRC2)
= 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). 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)
Rb (retinoblastoma protein) RB1 (associates with histone deacetylase-1 and -2)
RCOR (REST corepressor)
RCOR1 (RCOR1)
RCOR2 (RCOR2)
RCOR3 (RCOR3)
Sin3
SIN3A (SIN3A)
SIN3B (SIN3B)
TIF1 (transcriptional intermediary factor 1)
TRIM24 Tripartite motif-containing 24 (TRIM24)
TRIM28 Tripartite motif-containing 28 (TRIM28)
TRIM33 Tripartite motif-containing 33 (TRIM33)
= Dual function activator/repressors
=NSD1 (NSD1)
PELP-1 (proline, glutamic acid and leucine rich protein 1) PELP1
RIP140 (receptor-interacting protein 140) NRIP1
YAP
WWTR1 (TAZ)
ATP-dependent remodeling factors
SWI/SNF family
chromatin structure remodeling complex
ISWI protein SMARCA1, SMARCA2
See also
Coactivator (genetics)
Corepressor (genetics)
Nuclear receptor coregulators
RNA polymerase control by chromatin structure
Transcription
Transcription factor
TcoF-DB
References
External links
"Nuclear Receptor Signaling Atlas (Receptors, Coactivators, Corepressors and Ligands)". The NURSA Consortium. Retrieved 2008-02-21. an NIH-funded research consortium and database; includes open-access PubMed-indexed journal, Nuclear Receptor Signaling
Kata Kunci Pencarian:
- LPXN
- Transcription coregulator
- Transcription (biology)
- Gal4 transcription factor
- Coactivator (genetics)
- Pparg coactivator 1 alpha
- NSD1
- Nuclear receptor coregulators
- Selective androgen receptor modulator
- Calreticulin
- Transcription factor
