Built by association: structure and function of helix-loop-helix DNA-binding proteins

The transcription of genes in eukaryotic cells is controlled by a complex system of protein factors that interact both with each other and with DNA. A critical step in gene activation is binding of such transcription factors to specific DNA sequences. These DNA-binding proteins vary greatly in size and sequence, but frequently contain sequence motifs corresponding to one of a limited set of classes of DNA-binding domains. One example, the ‘helix-loop-helix’ domain (HLH), consists of two α-helices separated by a loop, and was first identified in an immunoglobulin enhancer binding factor, and other regulatory proteins [1]. The sequence of HLH domains is highly conserved, and they occur in a wide range of diverse regulatory proteins found in eukaryotes from yeast to humans. Most known HLH domains are of the b/HLH type, which have a conserved basic region (b) that is immediately amino-terminal to the HLH itself and that is required for DNA binding. Several also contain a second common DNA-binding motif, the ‘leucine zipper’ (Z) [2], immediately carboxy-terminal to the HLH and are therefore called b/HLH/Z domains. Sequences for a number of HLH proteins, mostly transcriptional activators, are shown in Figure 1.