10.4: Cooperative Binding of Transcription Regulators

Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome. Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form dimers that bind to a sequence twice as long as a monomer binds, increasing the sequences and reducing the chances of random binding. Transcription regulator dimers can be homodimers or heterodimers. In solution, these cooperative regulators exist either as monomers or weakly linked dimers. However, when these monomers bind to an extended cis-regulatory sequence on the DNA, they form stable dimers.

Cooperativity is a phenomenon where the binding of a monomeric protein causes structural changes to the DNA and increases the regulatory sites’ affinity for other monomers. This enables the monomers to bind as dimers on the cis-regulatory sequence. This phenomenon also helps regulators access sites located on DNA that is tightly bound to histone proteins in the nucleosome, which would otherwise be inaccessible. The first binding usually occurs at the DNA at the end of the nucleosome, where it is not tightly bound. Binding at this site leads to the DNA moving away from the histones, thereby leading to the unpacking of the nucleosome. This unpacking increases access to the other regulatory sites. In eukaryotes, transcription factor binding predominantly depends on cooperativity. Although cooperativity can occur in some cases, most of the binding of transcriptional regulators in prokaryotes is non-cooperative. In such cases, the regulators exist as stable dimers held together by several non-covalent interactions.

Whether an unknown regulator binds cooperatively or non-cooperatively can be determined by plotting the number of occupied binding sites on the DNA against the protein concentration. If the plot is an S-shaped curve, it indicates that the regulator binds cooperatively to the binding sites. If the curve rises steadily before leveling off as it approaches all of the binding sites being occupied, it indicates that binding is non-cooperative.

Transcriptional regulators are proteins that recognize and bind to short sequences of DNA known as cis-regulatory sequences. Because these sequences are usually less than ten nucleotides long, the chances of the same sequence randomly occurring in the genome are very high.

Many regulators form a dimer pair in order to limit binding to random sequences. A dimer can bind sequences longer than ten nucleotides making it less likely that the sequence will be randomly present in the genome and increasing the binding specificity.

These regulatory dimers can either be a homodimer made of the same types of monomer or a heterodimer with different types of monomers.  Because the pairs can be composed of different monomers, the various combinations allow binding to different sequences without needing new types of proteins.

When not bound to DNA, cooperative regulators exist as monomers that sometimes form dimers through weak, non-covalent interactions; however, these structures form tightly associated dimers when bound to DNA due to cooperative binding.

Cooperative binding is a phenomenon where the binding of a monomer to the cis-regulatory sequence increases the likelihood of a second regulator binding due to structural changes. This allows a second regulator to bind tightly to the other side of the binding site and form a dimer with the first.

This means that most of the time either all instances of specific cis-regulatory sequences have a regulator bound or none of them do. 

For many genes, the DNA is wrapped tightly around histone proteins preventing transcriptional regulators from accessing the cis-regulatory sequences. However, the loosely bound end of the DNA allows some room for binding. The binding of a single regulator at this site can help to unwind the structure, thereby allowing the other regulators to bind.