The DNA-binding domains of eukaryotic transcription fac tors contain a variety of structural motifs that bind specific DNA sequences. The ability of DNA-binding proteins to bind to specific DNA sequences commonly results from noncovalent interactions between atoms in an α helix in the DNA-binding domain and atoms on the edges of the bases within the major groove in the DNA. Ionic interactions between positively charged residues arginine and lysine and negatively charged phosphates in the sugar-phosphate back bone, and in some cases, interactions with atoms in the DNA minor groove, also contribute to binding.

The principles of specific protein-DNA interactions were first discovered during the study of bacterial repressors. Many bacterial repressors are dimeric proteins in which an α helix from each monomer inserts into the major groove in the DNA helix and makes multiple, specific interactions with the atoms there (Figure 1). This α helix is referred to as the recognition helix or sequence-reading helix because most of the amino acid side chains that con tact bases in the DNA extend from this helix. The recognition helix, which protrudes from the surface of a bacterial repressor, is usually supported in the protein structure in part by hydrophobic interactions with a second α helix just N-terminal to it. This entire structural element, which is present in many bacterial repressors, is called a helix-turn helix motif.

Fig1. Interaction of bacteriophage 434 repressor with DNA. Ribbon diagram of 434 repressor bound to its specific operator DNA. The recognition helices are shown in green. The α helices N-terminal to the recognition helix and the turn in the polypeptide backbone between the helices in the helix-turn-helix structural motif are shown in yellow and red, respectively. The protein interacts intimately with one side of the DNA molecule over a length of 1.5 turns. [Data from A. K. Aggarwal et al., 1988, Science 242:899, PDB ID 2ori.]

Many additional structural motifs that can present an α helix to the major groove of DNA are found in eukaryotic transcription factors, which are often classified according to the type of DNA-binding domain they contain. Because most of these motifs have characteristic consensus amino acid sequences, potential transcription factors can be recognized among the cDNA sequences from various tissues that have been characterized in humans and other species. Here we introduce several common classes of DNA-binding proteins whose three-dimensional structures have been determined. In all these examples, and in many other transcription fac tors, at least one α helix is inserted into the major groove of DNA. However, some transcription factors contain alternative structural motifs (e.g., β strands and loops) that interact with DNA.

Homeodomain Proteins Many eukaryotic transcription fac tors that function during development contain a conserved 60-residue DNA-binding motif, called a homeodomain, that is similar to the helix-turn-helix motif of bacterial repressors. These transcription factors were first identified in Drosophila mutants in which one body part was transformed into another during development. The con served homeodomain sequence has also been found in vertebrate transcription factors, including those that have similar master-control functions in human development.

Zinc-Finger Proteins A number of different eukaryotic proteins have regions that fold around a central Zn2+ ion, producing a compact domain from a relatively short length of polypeptide chain. Termed a zinc finger, this structural motif was first recognized in DNA-binding domains, but is now known to occur in other proteins that do not bind to DNA. Here we describe two of the several classes of zinc-finger motifs that have been identified in eukaryotic transcription factors.

The C₂H₂ zinc finger is the most common DNA-binding motif encoded in the human genome and the genomes of other mammals. It is also common in multicellular plants, but is not the dominant type of DNA-binding domain in plants, as it is in animals. This motif has a 23–26-residue consensus sequence containing two conserved cysteine (C) and two conserved histidine (H) residues, whose side chains bind one Zn²⁺ ion. The name “zinc fin ger” was coined because a two-dimensional diagram of the structure resembles a finger. When the three-dimensional structure was solved, it became clear that the binding of the Zn²⁺ ion by the two cysteine and two histidine residues folds the relatively short polypeptide sequence into a compact domain, which can insert its α helix into the major groove of DNA. Many transcription factors contain multiple C2H2 zinc fingers, which interact with successive groups of base pairs, within the major groove, as the protein wraps around the DNA double helix (Figure 2a).

Fig2. Eukaryotic DNA-binding domains that use an

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مواضيع ذات صلة

Promoter-Proximal Elements Help Regulate Eukaryotic Genes

Elongation Factors Regulate the Initial Stages of Transcription in the Promoter-Proximal Region

General Transcription Factors Position RNA Polymerase II at Start Sites and Assist in Initiation

Microarrays (DNA Chips)

Analysing Genetic Mutations and Polymorphisms

The Largest Subunit in RNA Polymerase II Has an Essential Carboxy-Terminal Repeat

Three Eukaryotic RNA Polymerases Catalyze Formation of Different RNAs

Regulatory Elements in Eukaryotic DNA Are Found Both Close to and Many Kilobases Away from Transcription Start Sites

Control of Gene Expression in Bacteria

Nucleic Acid Electrophoresis

Analysing Genes and Gene Expression

Screening Gene Libraries