Modular Structure of Transcription Factors

1. Modular Structure of Transcription Factors

2. Transcription is an important step in gene expression that is regulated by the concerted action of numerous transcription factors. These factors are proteins that recognize specific promoter sequences and generally bind to them as homo- or heterodimers. Characteristically, transcription factors have two functional components: a DNA-binding domain and a transactivation domain. DNA Binding DomainsTranscription factors are classified according to the structure of the DNA-binding domain including basic helix-loop-helix, zinc finger, leucine zipper or high mobility group. The basic helix-loop-helix structure contains two amphipathic -helices with highly conserved basic residues on the amino-terminal side and several hydrophobic residues on the carboxy-terminal end. The helices are linked by amino acid sequences of variable length, which form reverse turns and loops and the entire motif mediates homo- and heterodimerization, which favors DNA-binding through the basic domains. Zinc finger transcription factors must recruit zinc in order to bind to DNA. There are two zinc finger motifs that have been identified. The first consists of 30 amino acids, including two cysteine-histidine pairings that coordinate tetrahedral binding to a single zinc atom. The second zinc finger motif displays a partnership between cysteine-cysteine residues to direct zinc chelation. The leucine zipper motif mediates DNA association in many different transcription factors including the proto-oncogene c-Myc, c-Fos and c-Jun. Like many other transcription factors, the leucine-zipper-containing transcription factors bind DNA as dimers. A leucine zipper is formed by two -helices, one from each monomer. The helices are held together by hydrophobic interactions between leucine residues, which are located on one side of each helix. The high mobility group box defines a class of transcription factors. It binds to a 20bp span of DNA and distorts DNA structure. This motif is also a feature of many structural and non-chromosomal proteins in the nucleus and can mediate bending, wrapping, spacing and coiling of DNA. Modular Structure of Transcription Factors

3. Transactivation DomainsFollowing DNA binding, a transcription factor exerts an influence over gene expression. This is done through interaction with other transcription factors or with the basal transcriptional machinery in order to affect the efficiency of formation or binding of the transcription complex. These associations are often mediated through a transactivation domain, which in most cases ranges from 30-100 amino acids in length and contain variable functional amino acid arrangements such as glutamine- or proline-rich regions. Transactivation domains may act directly or they may recruit coactivator proteins that possess activation properties and an ability to interact with the basal transcription machinery, but these proteins lack any intrinsic DNA-binding capacity. For example, cAMP responsive element binding protein (CREB) associates with CREB binding protein (CBP), which in turn enhances gene transcription through activation of TFIIB. Alternatively, some transcription factors mediate their effects by simply binding DNA and transmitting conformational changes through chromatin structure. By doing this the transcription factor improves the accessibility of proteins to DNA binding sites. Modular Structure of Transcription Factors