Transcription coregulator
Encyclopedia
In molecular biology
and genetics
, transcription coregulators are protein
s that interact with transcription factor
s 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 histone
s. A second ATP
dependent class modifies the conformation of chromatin.
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) enzyme
s 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 transcription
al corepressor for transcription factors in the nuclear receptor
family such as glucocorticoid receptor
s.
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
and genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, transcription coregulators are protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that interact with transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s to either activate or repress the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
while those that repress are known as corepressors
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
. The mechanism of action of transcription coregulators is to modify chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
structure and thereby make the associated DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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 histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
s. A second ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
dependent class modifies the conformation of chromatin.
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 deprotonatedDeprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...
which gives DNA a net negative charge. Histones are rich in lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residues which at physiological pH are protonated
Protonation
In chemistry, protonation is the addition of a proton to an atom, molecule, or ion. Some classic examples include*the protonation of water by sulfuric acid:*the protonation of isobutene in the formation of a carbocation:2C=CH2 + HBF4 → 3C+ + BF4−*the protonation of ammonia in the...
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
Histone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....
(HAT) catalytic activity or recruit other proteins with this activity to promoters. These HAT proteins are able to acetylate
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
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
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
(HDAC) enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s 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
PELP-1
PELP-1 is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.-Activation of protein kinases:...
can act as a transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
al corepressor for transcription factors in the nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
family such as glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
s.
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)
- ARA54RNF14E3 ubiquitin-protein ligase RNF14 is an enzyme that in humans is encoded by the RNF14 gene.-Interactions:RNF14 has been shown to interact with Androgen receptor.-Further reading:...
- ARA55TGFB1I1Transforming growth factor beta-1-induced transcript 1 protein is a protein that in humans is encoded by the TGFB1I1 gene.-Interactions:TGFB1I1 has been shown to interact with PTPN12, PTK2, Androgen receptor, PTK2B, Dopamine transporter and Hsp27....
- ARA70NCOA4Nuclear receptor coactivator 4 is a protein that in humans is encoded by the NCOA4 gene.-Interactions:NCOA4 has been shown to interact with Peroxisome proliferator-activated receptor gamma and Androgen receptor.-Further reading:...
- ARA54
- BCAS3BCAS3Breast carcinoma amplified sequence 3, also known as BCAS3, is a protein which in humans is encoded by the BCAS3 gene. BCAS3 is a gene that is amplified and overexpressed in breast cancer cells.- Function :...
(breast carcinoma amplified sequence 3)
- CREB-binding protein
- CRTC (CREB regulated transcription coactivator)
- CRTC1CRTC1CREB-regulated transcription coactivator 1 , previously referred to as TORC1 is a protein that in humans is encoded by the CRTC1 gene...
- CRTC2CRTC2CREB regulated transcription coactivator 2, also known as CRTC2, is a protein which in humans is encoded by the CRTC2 gene.- Function :...
- CRTC3CRTC3CREB-regulated transcription coactivator 3 is a protein that in humans is encoded by the CRTC3 gene....
- CRTC1
- CARM1CARM1CARM1 is an enzyme encoded by the gene found in human beings, as well as many other mammals. It has a polypeptide chain type that is 348 residues long, and is made up of alpha helices and beta sheets...
(coactivator-associated arginine methyltransferase 1) - Nuclear receptor coactivator (NCOA)
- NCOA1/SRC-1 (steroid receptor coactivator-1)/
- NCOA2/GRIP1 (glucocorticoid receptor interacting protein 1)/ TIF2 (transcriptional intermediary factor 2)
- NCOA3/AIB1 (amplified in breast)
- NCOA4NCOA4Nuclear receptor coactivator 4 is a protein that in humans is encoded by the NCOA4 gene.-Interactions:NCOA4 has been shown to interact with Peroxisome proliferator-activated receptor gamma and Androgen receptor.-Further reading:...
/ARA70 (androgen receptor associated protein 70) - NCOA5NCOA5Nuclear receptor coactivator 5 , also known as coactivator independent of AF-2 function , is a protein that in humans is encoded by the NCOA5 gene.- Function :...
- NCOA6NCOA6Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.-Interactions:NCOA6 has been shown to interact with Ku70, RBBP5, E2F1, Retinoblastoma protein, CREB-binding protein, Activating transcription factor 2, HSF1, HBXIP, TGS1, TUBB, TUBA4A, Thyroid hormone receptor...
- NCOA7NCOA7Nuclear receptor coactivator 7 is a protein that in humans is encoded by the NCOA7 gene.-External links:...
- p300EP300E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...
- PCAFPCAFP300/CBP-associated factor , also known as K acetyltransferase 2B , is a human gene and trancriptional coactivator associated with p53.-Structure:...
(p300/CBP associating factor) - PGC1 (proliferator activated receptor gamma coactivator 1)
- PPARGC1APPARGC1APeroxisome proliferator-activated receptor gamma coactivator 1-alpha is a protein that in humans is encoded by the PPARGC1A gene....
- PPARGC1BPPARGC1BPeroxisome proliferator-activated receptor gamma coactivator 1-beta is a protein that in humans is encoded by the PPARGC1B gene.-Further reading:...
- PPARGC1A
- PNRC (proline-rich nuclear receptor coactivator 1)
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, copressors bind preferentially to the apo (ligand free) form of the nuclear receptor (or possibly antagonist bound receptor).- CtBPSIN3APaired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.-Interactions:SIN3A has been shown to interact with HDAC9, OGT, RBBP7, RBBP4, Host cell factor C1, MXD1, IKZF1, Nuclear receptor co-repressor 2, SAP130, KLF11, Methyl-CpG-binding domain protein 2, HDAC1,...
602618 (associates with class II histone deacetylases) - LCoRLCORLigand-dependent corepressor is a protein that in humans is encoded by the LCOR gene.- Function :LCOR is a transcriptional corepressor widely expressed in fetal and adult tissues that is recruited to agonist-bound nuclear receptors through a single LxxLL motif, also referred to as a nuclear...
(ligand-dependent corepressor) - Nuclear receptor CO-Repressor (NCOR)
- NCOR1Nuclear receptor co-repressor 1The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 is a protein that in humans is encoded by the NCOR1 gene....
- NCOR2Nuclear receptor co-repressor 2The nuclear receptor co-repressor 2 is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target...
/SMRT (Silencing Mediator (co-repressor) for Retinoid and Thyroid-hormone receptors) (associates with histone deacetylase-3)
- NCOR1
- RbRetinoblastoma proteinThe retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(retinoblastoma protein) (associates with histone deacetylase-1 and -2) - RCOR (REST corepressor)
- RCOR1RCOR1REST corepressor 1 is a protein that in humans is encoded by the RCOR1 gene.-Interactions:RCOR1 has been shown to interact with HMG20B, HDAC1, Histone deacetylase 2, RE1-silencing transcription factor and PHF21A.-Further reading:...
- RCOR2
- RCOR3
- RCOR1
- Sin3
- SIN3ASIN3APaired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.-Interactions:SIN3A has been shown to interact with HDAC9, OGT, RBBP7, RBBP4, Host cell factor C1, MXD1, IKZF1, Nuclear receptor co-repressor 2, SAP130, KLF11, Methyl-CpG-binding domain protein 2, HDAC1,...
- SIN3BSIN3BPaired amphipathic helix protein Sin3b is a protein that in humans is encoded by the SIN3B gene.-Interactions:SIN3B has been shown to interact with HDAC1, Zinc finger and BTB domain-containing protein 16, SUDS3 and IKZF1.-Further reading:...
- SIN3A
- TIF1 (transcriptional intermediary factor 1)
- TRIM24TRIM24Tripartite motif-containing 24 also known as transcriptional intermediary factor 1α is a protein that, in humans, is encoded by the TRIM24 gene.- Function :...
Tripartite motif-containing 24 - TRIM28TRIM28Tripartite motif-containing 28 also known as transcriptional intermediary factor 1β is a protein that in humans is encoded by the TRIM24 gene.- Function :...
Tripartite motif-containing 28 - TRIM33TRIM33Tripartite motif-containing 33 also known as transcriptional intermediary factor 1 gamma , is a human gene.The protein encoded by this gene is thought to be a transcriptional corepressor...
Tripartite motif-containing 33
- TRIM24
Dual function activator/repressors
- NSD1NSD1NSD1 is a transcription coregulator protein associated with Sotos syndrome and Weaver syndrome.-External Links:*...
- PELP-1PELP-1PELP-1 is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.-Activation of protein kinases:...
(proline, glutamic acid and leucine rich protein 1) - RIP140NRIP1Nuclear receptor-interacting protein 1 is a protein that in humans is encoded by the NRIP1 gene.RIP140 has an important role in regulating lipid and glucose metabolism, and regulates gene expression in metabolic tissues including heart, skeletal muscle, and liver.Knockout mice that completely lack...
(receptor-interacting protein 140)
ATP-dependent remodeling factors
- SWI/SNFSWI/SNFSWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
family - chromatin structure remodeling complexChromatin Structure Remodeling (RSC) ComplexRSC is a 17-subunit complex with the capacity to remodel the structure of chromatin. It exhibits a DNA-dependent ATPase activity stimulated by both free and nucleosomal DNA and a capacity to perturb nucleosome structures...
- ISWI protein ,
See also
- Coactivator (genetics)Coactivator (genetics)A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
- Corepressor (genetics)Corepressor (genetics)In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
- Nuclear receptor coregulatorsNuclear receptor coregulatorsNuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily...
- RNA polymerase control by chromatin structure
- TranscriptionTranscription (genetics)Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
- Transcription factorTranscription factorIn molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
- TcoF-DBTcoF-DBThe Dragon Database for Human Transcription Co-Factors and Transcription Factor Interacting Proteins is a database that facilitates the exploration of proteins involved in the regulation of transcription in humans by binding to regulatory DNA regions and proteins involved in the regulation of...