A SINGLE RESIDUE WITHIN THE HOMEODOMAIN OF THE BRN-3 POU FAMILY TRANSCRIPTION FACTORS DETERMINES WHETHER THEY ACTIVATE OR REPRESS THE SNAP-25 PROMOTER

THE closely related POU family transcription factors Brn-3a and Brn-3b differ in their effect on a number of different neuronally expressed promoters such as that of the gene encoding the synaptic vesicle compo nent SNAP-25. Thus Brn-3a activates these promoters whilst Brn-3b repr esses both their basal activity and their activation by Brn-3a. We sho w here that alterations of a single amino acid at position 22 in the P OU-homeodomain from the isoleucine found in Brn-3b to the valine found at the equivalent position in Brn-3a converts Brn-3b from a repressor to an activator of the SNAP-25 gene promoter. The converse mutation i n Brn-3a abolishes its ability to activate the SNAP-25 gene promoter a nd allows it to repress the basal activity of the promoter and its act ivation by wild type Brn-3a. This is the first time that a single amin o acid change has been shown to convert an activator of a naturally oc curring promoter to a repressor and vice versa. These results are disc ussed in terms of the critical role of position 22 in the POU homeodom ain in the protein-protein interactions of POU proteins.