DNA Binding Domains of Transcription Factors

Overview: Details about the various DNA binding domains of transcription factors including about their structure, function, and ways of ensuring sufficient regulatory diversity.

Transcription factors whether activator or repressor have DNA-binding domains with structural motifs that bind specific DNA sequences.  The binding commonly results from noncovalent interactions, between the alpha helices of the protein's DNA binding domain and atoms on the bases in the major groove of the DNA helix. The positively charged amino acids can interact with the with the negatively charged backbone of the DNA. Hence, this is a charged-based, or ionic, interaction. Several different motifs of DNA-binding domains are known.

Zinc-Finger Motifs 

In brief, these are protein regions that fold around a central Zn+2 ion.

C2H2 zinc finger: 
These are most commonly found in humans. The binding of the zinc ion occurs by two cysteine and two histidine residues in the domain, which allow the insertion of the a-helix (a barrel-like structure) into the major groove of the DNA of the enhancer element. They contain 3 or more repeating finger units and bind as monomers to the DNA sequence. Since a monomer is only one protein, there is no symmetry.

C4 zinc finger: 
These are only found in around 50 human transcription factors of the nuclear receptor family. Nuclear receptors are a class of proteins which are found in cells and sense steriod and thyroid hormones. Unlike C2H2 zinc fingers, C4 zinc fingers contain only two finger units, and bind as homodimers - two identical macromolecules. This allows them to have two-fold rotational symmetry, meaning the second is a mirror image of itself, and they bind to consensus DNA sequences that are inverted repeats.

Other Types of DNA-Binding Domains

Leucine-zipper:
They are characterized by having a leucine residue in every seventh position of the protein sequence, therefore they exhibit periodicity. Since, the protein has hydrophobic amino acid interactions, two proteins will interact in a coil-coil domain region, with leucine on either side to form a hydrophobic pocket, giving it the stability to dimerize. What is important to remember about leucine-zippers is that they are heterodimers (two different proteins) with basic amino acids possessing an enriched net positive charge that are capable of interacting with the phosphate backbone of the major groove of DNA. Also, Leucine-zippers belong to a larger family of related proteins known as "basic zippers" or bZip, which have similar hydrophobic interactions, but just with different hydrophobic amino acids.

Basic Helix-Loop-Helix (bHLH)
In structure, the Basic Helix-Loop-Helix is similar to the bZip, however a nonhelical loop separates two a-helical regions. This non-helical region doesn't not necessarily have a function, it is just a structural feature of which to be aware. Different bHL proteins can also form heterodimers.

A more interesting topic and question to consider is the following (drum roll please):

How can the finite set of transcription factors generate enough regulatory diversity?

Well, in a few ways. By the use of heterodimers, inhibitory factors, and cooperative binding. Please note that this list is probably not all inclusive, full meal combo done deal.

1) Heterodimers
Since each monomer has different DNA-binding specificity, combining two different monomers to make a heterodimer, increases diversity by becoming a problem of combinatorics, which is pretty sweet.

2) Inhibitory factors
The protein can block DNA binding by using some bZip and bHLH monomers, preventing expression of genes. Also, the inhibitory factor interacts with the transcription factor, preventing it from forming a homodimer or heterodimer with factors available.

3) Cooperative Binding
Two independent transcription factors with different protein complexes bind to their independent transcription elements, which are in close proximity to each other. Separately they have weak affinity to DNA, but when both are present, they share strong cooperative binding at the enhancer region.