Self-assembly of the bZIP transcription factor ΔFosB

Delta FosB is a highly stable transcription factor that accumulates in specific brain regions upon chronic exposure to drugs of abuse, stress, or seizures, and mediates lasting behavioral responses. Delta FosB reportedly heterodimerizes with JunD forming a canonical bZIP leucine zipper coiled coil that clamps onto DNA. However, the striking accumulation of Delta FosB protein in brain upon chronic insult has brought its molecular status into question. Here, we demonstrate through a series of crystal structures that the Delta FosB bZIP domain self-assembles into stable oligomeric assemblies that defy the canonical arrangement. The Delta FosB bZIP domain also self-assembles in solution, and in neuron-like Neuro 2a cells it is trapped into molecular arrangements that are consistent with our structures. Our data suggest that, as Delta FosB accumulates in brain in response to chronic insult, it forms non-canonical assemblies. These species may be at the root of Delta FosB's striking protein stability, and its unique transcriptional and behavioral consequences.