Disordered activation domains enhance DNA target search rate of a bZIP transcription factor

Transcription factors typically contain an effector domain and a DNA-binding domain, and are predominantly disordered. There is increasing evidence that effector/activation domains contribute to the DNA target search process. However, exactly how those domains influence this search is still unclear. Here, we have purified full-length CREB, a bZIP transcription factor with long disordered activation domains. We found, using in-vitro stopped-flow kinetic and equilibrium binding experiments, that the full-length protein has high dimerization affinity and dimerizes before binding DNA, as recently shown for the standalone CREB bZIP domain. CREB contains three recognised intrinsically disordered activation domains, which fall into classical acidic and glutamine-rich classifications. We show that all three contribute to decrease CREBs general affinity for DNA. This, in turn, makes the target-search process more efficient by limiting CREB sequestration on non-target DNA. Thus, one of the ways in which intrinsically disordered, non-DNA-binding domains can affect target-search is by modulating non-specific DNA-binding affinity.