![Type ii nuclear receptor action](https://upload.wikimedia.org/wikipedia/commons/0/08/Type_ii_nuclear_receptor_action.png)
A coactivator is a type of
transcriptional coregulator that binds to an
activator (a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
) to increase the rate of
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of a
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
or set of genes.
The activator contains a
DNA binding domain
A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...
that binds either to a DNA
promoter site or a specific DNA
regulatory sequence
A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and vir ...
called an
enhancer.
Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
.
The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.
Some coactivators also have
histone acetyltransferase
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
(HAT) activity. HATs form large multiprotein complexes that weaken the association of
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
s to DNA by
acetylating the
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
histone tail. This provides more space for the transcription machinery to bind to the promoter, therefore increasing gene expression.
Activators are found in all living
organism
In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...
s, but coactivator proteins are typically only found in eukaryotes because they are more complex and require a more intricate mechanism for gene regulation.
In eukaryotes, coactivators are usually proteins that are localized in the nucleus.
Mechanism
![Histone acetylation and deacetylation](https://upload.wikimedia.org/wikipedia/commons/d/d0/Histone_acetylation_and_deacetylation.jpg)
Some coactivators indirectly regulate gene expression by binding to an activator and inducing a
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
that then allows the activator to bind to the DNA enhancer or promoter sequence.
Once the activator-coactivator complex binds to the enhancer, RNA polymerase II and other general transcription machinery are recruited to the DNA and transcription begins.
Histone acetyltransferase
Nuclear DNA
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. It ...
is normally wrapped tightly around histones, making it hard or impossible for the transcription machinery to access the DNA. This association is due primarily to the
electrostatic attraction
Coulomb's inverse-square law, or simply Coulomb's law, is an experimental law of physics that quantifies the amount of force between two stationary, electrically charged particles. The electric force between charged bodies at rest is conventiona ...
between the DNA and histones as the DNA
phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phospho ...
backbone is negatively charged and histones are rich in lysine residues, which are positively charged. The tight DNA-histone association prevents the transcription of DNA into RNA.
Many coactivators have histone acetyltransferase (HAT) activity meaning that they can acetylate specific
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues on the N-terminal tails of histones.
In this method, an activator binds to an enhancer site and recruits a HAT complex that then acetylates nucleosomal promoter-bound histones by neutralizing the positively charged lysine residues.
This charge neutralization causes the histones to have a weaker bond to the negatively charged DNA, which relaxes the chromatin structure, allowing other transcription factors or transcription machinery to bind to the promoter (transcription initiation).
Acetylation by HAT complexes may also help keep chromatin open throughout the process of elongation, increasing the speed of transcription.
![Protein-acetylation-nterminal](https://upload.wikimedia.org/wikipedia/commons/0/06/Protein-acetylation-nterminal.svg)
Acetylation of the N-terminal histone tail is one of the most common protein modifications found in eukaryotes, with about 85% of all human proteins being acetylated.
Acetylation is crucial for synthesis, stability, function, regulation and localization of proteins and RNA transcripts.
HATs function similarly to N-terminal acetyltransferases (NATs) but their acetylation is reversible unlike in NATs. HAT mediated histone acetylation is reversed using histone deactetylase (HDAC), which catalyzes the hydrolysis of lysine residues, removing the acetyl group from the histones.
This causes the chromatin to close back up from their relaxed state, making it difficult for the transcription machinery to bind to the promoter, thus repressing gene expression.
Examples of coactivators that display HAT activity include
CARM1
CARM1 (coactivator-associated arginine methyltransferase 1), also known as PRMT4 (protein arginine N-methyltransferase 4), is an enzyme () encoded by the gene found in human beings, as well as many other mammals. It has a polypeptide (L) chain t ...
,
CBP CBP may refer to:
Business parks
* Cebu Business Park, a central business district in Cebu City, Philippines
* Changi Business Park, an eco-friendly industrial park in Singapore
* Chiswick Business Park, a business park in Gunnersbury, West London
...
and
EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
.
Corepression
Many coactivators also function as
corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, b ...
s under certain circumstances.
Cofactors such as
TAF1
Transcription initiation factor TFIID subunit 1, also known as transcription initiation factor TFIID 250 kDa subunit (TAFII-250) or TBP-associated factor 250 kDa (p250), is a protein that in humans is encoded by the ''TAF1'' gene.
Function
Init ...
and
BTAF1
TATA-binding protein-associated factor 172 is a protein that in humans is encoded by the ''BTAF1'' gene.
Function
Initiation of transcription by RNA polymerase II requires the assistance of TATA box-binding protein (TBP; MIM 600075) and TBP-as ...
can initiate transcription in the presence of an activator (act as a coactivator) and repress basal transcription in the absence of an activator (act as a corepressor).
Significance
Biological significance
Transcriptional regulation is one of the most common ways for an organism to alter gene expression.
The use of activation and coactivation allows for greater control over when, where and how much of a protein is produced.
This enables each cell to be able to quickly respond to environmental or physiological changes and helps to mitigate any damage that may occur if it were otherwise unregulated.
Associated disorders
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s to coactivator genes leading to loss or gain of protein function have been linked to diseases and disorders such as
birth defects
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
,
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
(especially hormone dependent cancers),
neurodevelopmental disorder
Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...
s and
intellectual disability
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
(ID), among many others.
Dysregulation leading to the over- or under-expression of coactivators can detrimentally interact with many drugs (especially
anti-hormone drugs) and has been implicated in cancer,
fertility
Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...
issues and neurodevelopmental and
neuropsychiatric disorders
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...
.
For a specific example, dysregulation of
CREB-binding protein
Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...
(CBP)—which acts as a coactivator for numerous transcription factors within the central nervous system (CNS), reproductive system, thymus and kidneys—has been linked to
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
,
leukaemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
,
Rubinstein-Taybi syndrome, neurodevelopmental disorders and deficits of the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
,
hematopoiesis
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
and
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
function.
As drug targets
Coactivators are promising targets for drug therapies in the treatment of cancer,
metabolic disorder
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
,
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
and
type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
, along with many other disorders.
For example, the steroid receptor coactivator (SCR)
NCOA3
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the ''NCOA3'' gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone recept ...
is often overexpressed in
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
, so the development of an inhibitor molecule that targets this coactivator and decreases its expression could be used as a potential treatment for breast cancer.
Because transcription factors control many different biological processes, they are ideal targets for drug therapy.
The coactivators that regulate them can be easily replaced with a synthetic ligand that allows for control over an increase or decrease in gene expression.
Further technological advances will provide new insights into the function and regulation of coactivators at a whole-organism level and elucidate their role in human disease, which will hopefully provide better targets for future drug therapies.
Known coactivators
To date there are more than 300 known coregulators.
Some examples of these coactivators include:
*
ARA54 targets
androgen receptor
The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
s
*
ATXN7L3 targets several members of the
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
superfamily
*
BCL3
B-cell lymphoma 3-encoded protein is a protein that in humans is encoded by the ''BCL3'' gene.
This gene is a proto-oncogene candidate. It is identified by its translocation into the immunoglobulin alpha-locus in some cases of B-cell leukemia. ...
targets 9-cis retinoic acid receptor (RXR)
*
CBP CBP may refer to:
Business parks
* Cebu Business Park, a central business district in Cebu City, Philippines
* Changi Business Park, an eco-friendly industrial park in Singapore
* Chiswick Business Park, a business park in Gunnersbury, West London
...
targets many transcription factors
*
CDC25B
M-phase inducer phosphatase 2 is an enzyme that in humans is encoded by the ''CDC25B'' gene.
CDC25B is a member of the CDC25 family of phosphatases. CDC25B activates the cyclin dependent kinase CDC2 by removing two phosphate groups and it is requi ...
targets
steroid receptors
Steroid hormone receptors are found in the cell nucleus, nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid h ...
*
COPS5 targets several nuclear receptors
*
DDC targets androgen receptors
*
EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
targets many transcription factors
*
KAT5
Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the ''KAT5'' gene. It is also commonly identified as TIP60.
The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was origina ...
targets many nuclear receptors
*
KDM1A
Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein in humans that is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-me ...
targets androgen receptors
* Steroid receptor coactivator (SRC) family
**
NCOA1
The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...
targets several members of the nuclear receptor superfamily
**
NCOA2 NCOA may refer to:
*National Change Of Address database (see United States Postal Service)
*National Chamber Orchestra of Armenia
*National Council on Aging
* The Non-commissioned officer, Noncomissioned Officer Academy in the United States Air For ...
targets several members of the nuclear receptor superfamily
**
NCOA3
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the ''NCOA3'' gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone recept ...
targets several nuclear receptors and transcription factors
*
YAP
Yap ( yap, Waqaab) traditionally refers to an island group located in the Caroline Islands of the western Pacific Ocean, a part of Yap State. The name "Yap" in recent years has come to also refer to the state within the Federated States of Micr ...
targets transcription factors
*
WWTR1
WW domain-containing transcription regulator protein 1 (WWTR1), also known as Transcriptional coactivator with PDZ-binding motif (TAZ), is a protein that in humans is encoded by the ''WWTR1'' gene. WWTR1 acts as a transcriptional coregulator a ...
targets transcription factors
See also
*
Repressor
In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
*
Regulation of gene expression
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...
*
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 ...
*
Translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
*
TcoF-DB
The Dragon Database for Human Transcription Co-Factors and Transcription Factor Interacting Proteins (TcoF-DB) is a database that facilitates the exploration of proteins involved in the regulation of transcription in humans by binding to regulatory ...
References
External links
Nuclear Receptor Signalling Atlas(NIH-funded research consortium and database; includes open-access PubMed-indexed journal, ''Nuclear Receptor Signaling'')
TcoF - Dragon database of transcription co-factors and transcription factor interacting proteins
{{Transcription coregulators
Gene expression
Molecular genetics
Proteins
Transcription coregulators