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A transcriptional activator is a protein (
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 ...
) that increases
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 or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and, in some cases, are required for the transcription of genes to occur. Most activators are
DNA-binding protein DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for DNA#Base pairing, single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove ...
s that bind to
enhancers In genetics, an enhancer is a short (50–1500 bp) region of DNA that can be bound by proteins ( activators) to increase the likelihood that transcription of a particular gene will occur. These proteins are usually referred to as transcription ...
or promoter-proximal elements. The DNA site bound by the activator is referred to as an "activator-binding site". The part of the activator that makes protein–protein interactions with the general transcription machinery is referred to as an "activating region" or "activation domain". Most activators function by binding sequence-specifically to a regulatory DNA site located near a promoter and making protein–protein interactions with the general transcription machinery (
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...
and
general transcription factor General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites (Promoter (genetics), promoter) on DNA to activate Transcription (genetics), transcription ...
s), thereby facilitating the binding of the general transcription machinery to the promoter. Other activators help promote gene transcription by triggering RNA polymerase to release from the promoter and proceed along the DNA. At times, RNA polymerase can pause shortly after leaving the promoter; activators also function to allow these “stalled” RNA polymerases to continue transcription. The activity of activators can be regulated. Some activators have an allosteric site and can only function when a certain molecule binds to this site, essentially turning the activator on. Post-translational modifications to activators can also regulate activity, increasing or decreasing activity depending on the type of modification and activator being modified. In some cells, usually eukaryotes, multiple activators can bind to the binding-site; these activators tend to bind cooperatively and interact synergistically.


Structure

Activator proteins consist of two main domains: 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 to a DNA sequence specific to the activator, and an activation domain that functions to increase gene transcription by interacting with other molecules. Activator DNA-binding domains come in a variety of conformations, including the
helix-turn-helix Helix-turn-helix is a DNA-binding protein (DBP). The helix-turn-helix (HTH) is a major structural motif capable of binding DNA. Each monomer incorporates two α helices, joined by a short strand of amino acids, that bind to the major groove of D ...
,
zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
, and
leucine zipper A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...
among others. These DNA-binding domains are specific to a certain DNA sequence, allowing activators to turn on only certain genes. Activation domains also come in a variety of types that are categorized based on the domain's amino acid sequence, including
alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side c ...
-rich,
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
-rich, and acidic domains. These domains are not as specific, and tend to interact with a variety of target molecules. Activators can also have
allosteric site In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric sit ...
s that are responsible for turning the activators themselves on and off.


Mechanism of action


Activator binding to regulatory sequences

Within the grooves of the DNA double helix,
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
s of the base pairs are exposed. The sequence of the DNA thus creates a unique pattern of surface features, including areas of possible
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
ing,
ionic bonding Ionic bonding is a type of chemical bonding that involves the electrostatic attraction between oppositely charged ions, or between two atoms with sharply different electronegativities, and is the primary interaction occurring in ionic compounds. ...
, as well as
hydrophobic interactions The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and exclude water molecules. The word hydrophobic literally means "water-fearing", and it describes the segregation of water and nonpolar ...
. Activators also have unique sequences of amino acids with side chains that are able to interact with the functional groups in DNA. Thus, the pattern of amino acid side chains making up an activator protein will be complementary to the surface features of the specific DNA regulatory sequence it was designed to bind to. The complementary interactions between the amino acids of the activator protein and the functional groups of the DNA create an “exact-fit” specificity between the activator and its regulatory DNA sequence. Most activators bind to the major grooves of the double helix, as these areas tend to be wider, but there are some that will bind to the minor grooves. Activator-binding sites may be located very close to the promoter or numerous base pairs away. If the regulatory sequence is located far away, the DNA will loop over itself (DNA looping) in order for the bound activator to interact with the transcription machinery at the promoter site. In prokaryotes, multiple genes can be transcribed together (
operon In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splic ...
), and are thus controlled under the same regulatory sequence. In eukaryotes, genes tend to be transcribed individually, and each gene is controlled by its own regulatory sequences. Regulatory sequences where activators bind are commonly found upstream from the promoter, but they can also be found downstream or even within
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
s in eukaryotes.


Functions to increase gene transcription

Binding of the activator to its regulatory sequence promotes gene transcription by enabling RNA polymerase activity. This is done through various mechanisms, such as recruiting transcription machinery to the promoter and triggering RNA polymerase to continue into elongation.


Recruitment

Activator-controlled genes require the binding of activators to regulatory sites in order to recruit the necessary transcription machinery to the promoter region. Activator interactions with RNA polymerase are mostly direct in prokaryotes and indirect in eukaryotes. In prokaryotes, activators tend to make contact with the RNA polymerase directly in order to help bind it to the promoter. In eukaryotes, activators mostly interact with other proteins, and these proteins will then be the ones to interact with the RNA polymerase.


= Prokaryotes

= In prokaryotes, genes controlled by activators have promoters that are unable to strongly bind to RNA polymerase by themselves. Thus, activator proteins help to promote the binding of the RNA polymerase to the promoter. This is done through various mechanisms. Activators may bend the DNA in order to better expose the promoter so the RNA polymerase can bind more effectively. Activators may make direct contact with the RNA polymerase and secure it to the promoter.


= Eukaryotes

= In eukaryotes, activators have a variety of different target molecules that they can recruit in order to promote gene transcription. They can recruit other transcription factors and
cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
that are needed in transcription initiation. Activators can recruit molecules known as coactivators. These coactivator molecules can then perform functions necessary for beginning transcription in place of the activators themselves, such as chromatin modifications. DNA is much more condensed in eukaryotes; thus, activators tend to recruit proteins that are able to restructure the chromatin so the promoter is more easily accessible by the transcription machinery. Some proteins will rearrange the layout of
nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...
s along the DNA in order to expose the promoter site ( ATP-dependent chromatin remodeling complexes). Other proteins affect the binding between histones and DNA via post-translational histone modifications, allowing the DNA tightly wrapped into nucleosomes to loosen. All of these recruited molecules work together in order to ultimately recruit the RNA polymerase to the promoter site.


Release of RNA polymerase

Activators can promote gene transcription by signaling the RNA polymerase to move beyond the promoter and proceed along the DNA, initiating the beginning of transcription. The RNA polymerase can sometimes pause shortly after beginning transcription, and activators are required to release RNA polymerase from this “stalled” state. Multiple mechanisms exist for releasing these “stalled” RNA polymerases. Activators may act simply as a signal to trigger the continued movement of the RNA polymerase. If the DNA is too condensed to allow RNA polymerase to continue transcription, activators may recruit proteins that can restructure the DNA so any blocks are removed. Activators may also promote the recruitment of elongation factors, which are necessary for the RNA polymerase to continue transcription.


Regulation of activators

There are different ways in which the activity of activators themselves can be regulated, in order to ensure that activators are stimulating gene transcription at appropriate times and levels. Activator activity can increase or decrease in response to environmental stimuli or other intracellular signals.


Activation of activator proteins

Activators often must be “turned on” before they can promote gene transcription. The activity of activators is controlled by the ability of the activator to bind to its regulatory site along the DNA. The DNA-binding domain of the activator has an active form and an inactive form, which are controlled by the binding of molecules known as
allosteric effector In biochemistry, an effector molecule is usually a small molecule that selectively binds to a protein and regulates its biological activity. In this manner, effector molecules act as ligands that can increase or decrease enzyme activity, gene e ...
s to the allosteric site of the activator. Activators in their inactive form are not bound to any allosteric effectors. When inactive, the activator is unable to bind to its specific regulatory sequence in the DNA, and thus has no regulatory effect on the transcription of genes. When an allosteric effector binds to the allosteric site of an activator, a conformational change in the DNA-binding domain occurs, which allows the protein to bind to the DNA and increase gene transcription.


Post-translational modifications

Some activators are able to undergo
post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
s that have an effect on their activity within a cell. Processes such as
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
,
acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...
, and
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
ation, among others, have been seen to regulate the activity of activators. Depending on the chemical group being added, as well as the nature of the activator itself, post-translational modifications can either increase or decrease the activity of an activator. For example, acetylation has been seen to increase the activity of some activators through mechanisms such as increasing DNA-binding affinity. On the other hand, ubiquitination decreases the activity of activators, as ubiquitin marks proteins for degradation after they have performed their respective functions.


Synergy

In prokaryotes, a lone activator protein is able to promote transcription. In eukaryotes, usually more than one activator assembles at the binding-site, forming a complex that acts to promote transcription. These activators bind
cooperatively Cooperation (written as co-operation in British English) is the process of groups of organisms working or acting together for common, mutual, or some underlying benefit, as opposed to working in competition for selfish benefit. Many animal a ...
at the binding-site, meaning that the binding of one activator increases the affinity of the site to bind another activator (or in some cases another transcriptional regulator) thus making it easier for multiple activators to bind at the site. In these cases, the activators interact with each other
synergistically Synergy is an interaction or cooperation giving rise to a whole that is greater than the simple sum of its parts. The term ''synergy'' comes from the Attic Greek word συνεργία ' from ', , meaning "working together". History In Christi ...
, meaning that the rate of transcription that is achieved from multiple activators working together is much higher than the additive effects of the activators if they were working individually.


Examples


Regulation of maltose catabolism

The breakdown of
maltose } Maltose ( or ), also known as maltobiose or malt sugar, is a disaccharide formed from two units of glucose joined with an α(1→4) bond. In the isomer isomaltose, the two glucose molecules are joined with an α(1→6) bond. Maltose is the two- ...
in ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' is controlled by gene activation. The genes that code for the enzymes responsible for maltose catabolism can only be transcribed in the presence of an activator. The activator that controls transcription of the maltose enzymes is “off” in the absence of maltose. In its inactive form, the activator is unable to bind to DNA and promote transcription of the maltose genes. When maltose is present in the cell, it binds to the allosteric site of the activator protein, causing a conformational change in the DNA-binding domain of the activator. This conformational change “turns on” the activator by allowing it to bind to its specific regulatory DNA sequence. Binding of the activator to its regulatory site promotes RNA polymerase binding to the promoter and thus transcription, producing the enzymes that are needed to break down the maltose that has entered the cell.


Regulation of the ''lac'' operon

The
catabolite activator protein Catabolite activator protein (CAP; also known as cAMP receptor protein, CRP) is a trans-acting transcriptional activator that exists as a homodimer in solution. Each subunit of CAP is composed of a ligand-binding domain at the N-terminus (CAPN, re ...
(CAP), otherwise known as
cAMP receptor protein cAMP receptor protein (CRP; also known as catabolite activator protein, CAP) is a regulatory protein in bacteria. CRP protein binds cAMP, which causes a conformational change that allows CRP to bind tightly to a specific DNA site in the promote ...
(CRP), activates transcription at the ''lac'' operon of the bacterium ''Escherichia coli''.
Cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP) is produced during glucose starvation; this molecule acts as an allosteric effector that binds to CAP and causes a conformational change that allows CAP to bind to a DNA site located adjacent to the lac promoter. CAP then makes a direct protein–protein interaction with RNA polymerase that recruits RNA polymerase to the lac promoter.


See also

*
Bacterial transcription Bacterial transcription is the process in which a segment of bacterial DNA is copied into a newly synthesized strand of messenger RNA (mRNA) with use of the enzyme RNA polymerase. The process occurs in three main steps: initiation, elongation, and ...
*
Coactivator (genetics) A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA p ...
*
Eukaryotic transcription Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Un ...
*
Glossary of gene expression terms A glossary (from grc, γλῶσσα, ''glossa''; language, speech, wording) also known as a vocabulary or clavis, is an alphabetical list of terms in a particular domain of knowledge with the definitions for those terms. Traditionally, a glo ...
*
Operon In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splic ...
*
Promoter (biology) In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of i ...
*
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 ...
*
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 ...
*
Squelching Squelching is a biological phenomenon in which a strong transcriptional activator acts to inhibit the expression of another gene. Squelching has been mostly studied in yeast, and most of the ideas regarding its mechanisms have come from research in ...
*
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 ...


References

{{DEFAULTSORT:Activator (Genetics) Transcription factors