DNA specificity enhanced by sequential binding of protein monomers

Transcriptional activation often requires the rapid assembly of complexes b etween dimeric transcription factors and specific DNA sites. Here we show t hat members of the basic region leucine zipper and basic region helix-loop- helix zipper transcription factor families follow an assembly pathway in wh ich two protein monomers bind DNA sequentially and form their dimerization interface while bound to DNA. Nonspecific protein or DNA competitors have l ittle effect on the rate of assembly along this pathway, but slow a competi ng pathway in which preformed dimers bind DNA. The sequential monomer-bindi ng pathway allows the protein to search for and locate a specific DNA site more quickly, resulting in greater specificity prior to equilibrium.