The specificity involved in the control of transcription requires that regulatory proteins bind with high affinity and specificity to the correct region of DNA. Three unique motifs—the helix-turn-helix (HTH), the zinc finger (ZF), and the leucine zipper (LZ)—account for many of these specific protein-DNA interactions. Examples of proteins containing these motifs are given in Table 1.

Table1. Examples of Transcription Factors That Contain Various DNA-Binding Motifs

Comparison of the binding activities of the proteins that contain these motifs leads to several important generalizations.

 1. Binding must be of high affinity to the specific site, and of low affinity to all other DNA.

 2. Small regions of the protein make direct contact with DNA; the rest of the protein, in addition to providing the trans-activation domains, may be involved in the dimerization of monomers of the binding protein, may provide a contact surface for the formation of heterodimers, may provide one or more ligand-binding sites, or may provide surfaces for interaction with coactivators, corepressors, or the transcription machinery.

 3. The protein-DNA interactions made by these proteins are maintained by hydrogen bonds, ionic interactions, and van der Waals forces.

4. The motifs found in these proteins are class-specific; their presence in a protein of unknown function suggests that the protein may bind to DNA.

5. Proteins with the helix-turn-helix or leucine zipper motifs form dimers, and their respective DNA-binding sites are symmetric palindromes. In proteins with the zinc finger motif, the binding site is repeated two to nine times. These features allow for cooperative interactions between binding sites and enhance the degree and affinity of binding.

The Helix-Turn-Helix Motif

The first motif described was the helix-turn-helix. Analysis of the 3D structure of the lambda cro transcription regulator revealed that each monomer consists of three antiparallel β sheets and three α helices (Figure 1). The dimer forms by association of the antiparallel β3 sheets. The α3 helices form the DNA recognition surface, and the rest of the molecule appears to be involved in stabilizing these structures. The average diameter of an α helix is 1.2 nm, which is the approximate width of the major groove in the B form of DNA.

Fig1. A schematic representation of the 3D structure of Cro protein and its binding to DNA by its helix-turn-helix motif (left). The cro monomer consists of three antiparallel β sheets (β1-β3 ) and three α helices (α1-α3 ). The helix-turn-helix (HTH) motif is formed because the α3 and α2 helices are held at about 90° to each other by a turn of four amino acids. The α3 helix of cro is the DNA recognition surface (shaded). Two monomers associate through interactions between the two antiparallel β3 sheets to form a dimer that has a twofold axis of symmetry (right). A cro dimer binds to DNA through its α3 helices, each of which contacts about 5 bp on the same face of the major groove. The distance between comparable points on the two DNA α helices is 34 Å, the distance required for one complete turn of the double helix. (Reproduced with permission from B Mathews.)

The DNA recognition domain of each cro monomer inter acts with 5 bp and the dimer-binding sites span 3.4 nm, allowing it to fit into successive half turns of the major groove on the same surface of DNA (see Figure 1). X-ray analyses of the λ cI repressor, CAP (the cAMP receptor protein of E. coli), tryptophan repressor, and phage 434 repressor, all also display this dimeric helix-turn-helix structure, which is also present in many eukaryotic DNA-binding proteins (see Table 1).

The Zinc Finger Motif

The zinc finger was the second DNA-binding motif whose atomic structure was elucidated. It was known that the eukaryotic protein involved, a positive regulator of 5S RNA gene transcription termed TFIIIA, required zinc for activity. Structural and biophysical analyses revealed that each TFIIIA molecule contains nine zinc ions in a repeating coordination complex formed by closely spaced cysteine–cysteine residues followed 12 to 13 amino acids later by a histidine–histidine pair (Figure 2). In some instances—notably the steroid thyroid nuclear hormone receptor family—the His–His doublet is replaced by a second Cys–Cys pair. The zinc finger motifs of the protein lie on one face of the DNA helix, with successive fingers alternatively positioned in one turn in the major groove. As is the case with the recognition domain in the helix-turn-helix protein, each TFIIIA zinc finger contacts about 5 bp of DNA. The importance of this motif in the action of steroid hormones is underscored by an “experiment of nature.” A single amino acid mutation in either of the two zinc fingers of the 1,25(OH)₂-D₃ receptor protein results in resistance to the action of this hormone and the clinical syndrome of rickets.

Fig2. Zinc fingers are a series of repeated domains (two to nine) in which each is centered on a tetrahedral coordination with zinc. In the case of the DNA-binding transcription factor TFIIIA, the coordination is provided by a pair of cysteine residues (C) separated by 12 to 13 amino acids from a pair of histidine (H) residues. In other zinc finger proteins, the second pair also consists of C residues. Zinc fingers bind in the major groove, where adjacent Zn-fingers make contact with 5 bp of DNA along the same face of the helix.

The Leucine Zipper Motif

Analysis of a 30-amino-acid sequence in the carboxyl-terminal region of the mammalian enhancer-binding protein C/EBP revealed a novel structure, the leucine zipper motif. As illustrated in Figure 3, this region of the protein forms an α helix in which there is a periodic repeat of leucine residues at every seventh position. This occurs for eight helical turns and four leucine repeats. Similar structures have been found in a number of other proteins associated with the regulation of transcription in all eukaryotes tested. This structure allows two identical or nonidentical monomers (eg, Jun–Jun or Fos–Jun) to “zip together” in a coiled coil and form a tight dimeric complex (see Figure 3). This protein–protein interaction serves to enhance the association of the separate DBDs with their target DNA sites (see Figure 3).

Fig3. The leucine zipper motif.(A) Shown is a helical wheel analysis of a carboxyl-terminal portion of the DNA-binding protein C/EBP. The amino acid sequence is displayed end-to-end down the axis of a schematic α helix . The helical wheel consists of seven spokes that correspond to the seven amino acids that comprise every two turns of the α helix. Note that leucine residues (L) occur at every seventh position (in this schematic C/EBP amino acid residues 1, 8, 15, 22; see arrow). Other proteins with “leucine zippers” have a similar helical wheel pattern. (B) A schematic model of the DNA-binding domain of C/EBP. Two identical C/EBP polypeptide chains are held in dimer formation by the leucine zipper domain of each polypeptide (denoted by the white rectangles and attached orange-shaded ovals). This association is required to hold the DNA-binding domains of each polypeptide (the green-shaded rectangles) in the proper conformation and register for DNA binding. (Reproduced with permission from S McKnight.)

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مواضيع ذات صلة

Reporter Genes Are Used to Define Enhancers & Other Regulatory Elements That Modulate Gene Expression

Certain DNA Elements Enhance or Repress Transcription of Eukaryotic Genes

Epigenetic Mechanisms Contribute Importantly to the Control of Gene Transcription

The Chromatin Template Contributes Importantly to Eukaryotic Gene Transcription Control

The Genetic Switch of Bacteriophage Lambda (λ) Provides Another Paradigm for Understanding the Role of Conditional Regulatory Protein-DNA Interactions in Transcriptional Control in Eukaryotic Cells

Analysis of Lactose Metabolism in E. coli Led to the Discovery of the Basic Principles of Gene Transcription

Biologic Systems Exhibit Three Types of Temporal Responses to a Regulatory Signal

Regulated Expression of Genes is Required for Development, Differentiation, & Adaptation

Posttranslational Processing Affects the Activity of many Proteins

Like Transcription, Protein synthesis can be described in three phases: Initiation, Elongation, & Termination

Mutations result when changes occur in the Nucleotide Sequence

The Genetic Code is Degenerate, Unambiguous, Nonoverlapping, Without Punctuation, & Universal