Design of a bZip Transcription Factor with Homo/Heterodimer-Induced DNA-Binding Preference

• Structures of the MafB and MafB/c-Fos allow direct comparison of bZip interactions
• Homodimeric MafB and heterodimeric MafB/c-Fos recognize different DNA motifs
• Rational engineering of bZip interactions allows changes of DNA-binding preference
• MafB/c-Fos protein/protein interactions and protein/DNA interactions are coupled

SummaryThe ability of basic leucine zipper transcription factors for homo- or heterodimerization provides a paradigm for combinatorial control of eukaryotic gene expression. It has been unclear, however, how facultative dimerization results in alternative DNA-binding repertoires on distinct regulatory elements. To unravel the molecular basis of such coupled preferences, we determined two high-resolution structures of the transcription factor MafB as a homodimer and as a heterodimer with c-Fos bound to variants of the Maf-recognition element. The structures revealed several unexpected and dimer-specific coiled-coil-heptad interactions. Based on these findings, we have engineered two MafB mutants with opposite dimerization preferences. One of them showed a strong preference for MafB/c-Fos heterodimerization and enabled selection of heterodimer-favoring over homodimer-specific Maf-recognition element variants. Our data provide a concept for transcription factor design to selectively activate dimer-specific pathways and binding repertoires.