title: Design of a bZip transcription factor with homo/heterodimer-induced DNA-binding preference.
abstract: The 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.
authors: EMBL Hamburg c/o DESY, Notkestraße 85, 22603 Hamburg, Germany.
authors: Vivian
authors: V
authors: Pogenberg
authors: EMBL Hamburg c/o DESY, Notkestraße 85, 22603 Hamburg, Germany.
authors: Larissa
authors: L
authors: Consani Textor
authors: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors: Laurent
authors: L
authors: Vanhille
authors: EMBL Hamburg c/o DESY, Notkestraße 85, 22603 Hamburg, Germany.
authors: Simon J
authors: SJ
authors: Holton
authors: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France; Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors: Michael H
authors: MH
authors: Sieweke
authors: EMBL Hamburg c/o DESY, Notkestraße 85, 22603 Hamburg, Germany. Electronic address: wilmanns@embl-hamburg.de.
authors: Matthias
authors: M
authors: Wilmanns
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D051258:MafB Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods; D055503:Protein Multimerization; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D004247:DNA