10.3.2 The Structural Economy of -Helical Motifs
10.3.2.1 The Helix-Turn-Helix Motif. The helix-turn-helixmotif was first characterized struc-
turally in regulatory proteins of bacteria and bacteriophage and appears to be both ancient and widely occur-
ring. Remarkably, many proteins that control transcription in eukaryotes also use a similar helix-turn-helix
reading head to that found in bacteria, and this is likely to have arisen by convergent evolution. A classical
example is the eukaryotic homeodomain, which forms a widely occurring family of factors whose members
are often involved in controlling the expression of genes of development, such as the engrailed homeo-
domain from the fruit fly Drosophila melanogaster (Figure 10.2a).
Another important transcription factor that contains a helix-turn-helix motif is the eukaryotic transcrip-
tion factor TFIIB, which is a component of a complex that binds roughly 30 bases ahead of the start site for
transcription. This highly conserved protein is also found in archaea (where it is known as TFB). TFIIB
forms a complex with the TBP (TATA Binding Protein) in which the DNA is highly distorted (Figure 10.5).
The helix-turn-helix motif recognizes a short element known as the 5-BRE that precedes the TATA element
(Section 6.6.3), where the pseudo-symmetric TBP binds, and thus defines the direction of transcription.
There are many variations on the theme of the helix-turn-helix fold that are found in both eukaryotes
and prokaryotes. It seems clear from the representative cases that the helix-turn-helix motif has evolved many
times within completely different protein frameworks, and, as noted by Janet Thornton, the motif is likely
to represent the convergent evolution of a stable solution to the problem of DNA recognition.
10.3.2.2 Leucine Zippers. The zipper proteins are dimeric transcription regulators that insert
-helices into the major groove of duplex DNA. One example is the protein domain called bZIP (Figure
10.2b). The bZIP domain, like many other transcription factors, binds as a homodimerto a palindromic
DNA sequence. bZIP has two protruding -helical DNA ‘reading heads’, and the motif from each monomer
is buried in the DNA major groove. The two reading heads make symmetry-equivalent interactions with base
pairs in two successive major grooves (half-sites). The dimer interface fixes the relative orientation of the
two reading heads so that each motif reads the same short DNA sequence on each of the two strands of the
palindromic site.
392 Chapter 10
Figure 10.5 The human TBP-protein binding to the TATA element (PDB: 1IFH). The protein has pseudo-dimeric
symmetry because of gene duplication of an ancestral precursor. The structure of the archaeal TBP is
very similar