Stimuli-responsive selection of target DNA sequences by synthetic bZIP peptides

Abstract

One of the strategies used by nature to regulate gene expression relies on the stimuli controlled combination of DNA-binding proteins. This in turn determines the target-binding site within the genome, and thereby whether a particular gene is activated or repressed. Here we demonstrate how a designed basic region leucine zipper-based peptide can be directed towards two different DNA sequences depending on its dimerization arrangement. While themonomeric peptide is non-functional, a C-terminal metallo-dimer recognizes the natural ATF/CREB-binding site (5'-ATGA cg TCAT-3'), and a N-terminal disulphide dimer binds preferentially to the swapped sequence (5-TCATcg ATGA-30'). As the dimerization mode can be efficiently controlled by appropriate external reagents, it is possible to reversibly drive the peptide to either DNA site in response to such specific inputs. This represents the firstexample of a designed molecule that can bind to more than one specific DNA sequence depending on changes in its environment.