How can transcription factors be so specific in the genes they target for regulation? This specificity comes from transcription factors having three major functional domains. The first is a DNA-binding domain, which recognizes a particular DNA sequence in the enhancer. There are several different types of DNA-binding domains, and they often designate the major family classifications for transcription factors. Some of the most common protein domains that convey DNA binding are homeodomain, zinc-finger, basic leucine zipper, basic helix-loop-helix, and helix-turn-helix (see Table 3.1). For instance, the homeodomain transcription factor Pax6 uses its paired DNA-binding domain to recognize the enhancer sequence, CAATTAGTCACGCTTGA (Aksan and Goding 1998; Wolf et al. 2009).1 In contrast, the MITF transcription factor contains both leucine zipper and helix-loop-helix domains, and it recognizes shorter DNA sequences called the E-box (CACGTG) and the M-box (CATGTG; Pogenberg et al. 2012).2 These sequences for MITF binding have been found in the regulatory regions of genes encoding several pigment-cell-specific enzymes of the tyrosinase family (Bentley et al. 1994; Yasumoto et al. 1994, 1997). Without MITF, these proteins are not synthesized properly, and melanin pigment is not made.
The second domain is a trans-activating domain, which activates or suppresses the transcription of the gene whose promoter or enhancer it has bound. Usually, this trans-activating domain enables the transcription factor to interact with the proteins involved in binding RNA polymerase II (such as TFIIB or TFIIE; see Sauer et al. 1995) or with enzymes that modify histones. When the MITF dimer is bound to its target sequence in the enhancer, its trans-activating domain is able to bind the transcriptional co-regulator p300/CBP. The p300/CBP protein is a histone acetyltransferase enzyme that loosens chromatin associated with genes that encode pigment-forming enzymes (Ogryzko et al. 1996; Price et al. 1998).
Finally, there is usually a protein-protein interaction domain, which allows the transcription factor’s activity to be modulated by transcriptional co-regulators or other transcription factors. As suggested above, MITF has a protein-protein interaction domain that enables it to dimerize with another MITF protein (Ferré-D’Amaré et al. 1993). The resulting homodimer (i.e., two identical protein molecules bound together) is the functional protein that binds to the DNA of enhancers of certain genes, thereby activating transcription (Figure 1).
1 Pax stands for “paired box,” and “box” refers to its DNA-binding domain. Pax proteins are homeodomain transcription factors that contain a paired domain for binding to DNA. Studies on Drosophila have shown that the loss of a homeodomain transcription factor causes dramatic homeotic transformations in structures, such as the transformation of an antenna into a leg.
2 E-box and M-box refer to “Enhancer” and “Myc,” respectively.
Figure 1 Three-dimensional model of the homodimeric transcription factor MITF (one protein shown in red, the other in blue) binding to a promoter element in DNA (white). The amino termini are located at the bottom of the figure and form the DNA-binding domains that recognize an 11-base-pair sequence of DNA having the core sequence CATGTG. The protein-protein interaction domain is located immediately above. MITF has the basic helix-loop-helix structure found in many transcription factors. The carboxyl-terminus of the molecule is thought to be the trans-activating domains that bind the p300/CBP transcription co-regulator.
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