Molecular Mechanisms Study Of BZIP Transcription Factor Combinatorial Regulation

Combinatorial regulation of gene expression is widely used by eukaryotes. In this process, the DNA-binding specificity of transcription factor is coupled with protein-protein interaction. However, the underlying molecular mechanisms remain largely unknown. In this work, a comprehensive theoretical analysis was performed to study the molecular mechanisms underlying the combinatorial regulation of the basic leucine zipper( bZIP) transcription factors. One position that participated in protein-protein interaction was determined to control the DNA-binding specificity of bZIP superfamily through bioinformatics analysis. The cAMP response element-binding protein(CREB)was then selected as a model system, molecular dynamics simulation revealed that the interaction was coupled with the Arg17-DNA interaction by controlling the flexibility and mobility of the spacer region, which determined the CREB DNA-binding specificity. Further structure analysis suggests the general existence of the Arg17-DNA interaction coupled combinatorial regulation mechanisms for the whole bZIP superfamily. The present work provides a meaningful molecular model for the combinatorial regulation of bZIP protein and may provide insights into the combinatorial regulation of other transcription factor superfamilies in eukaryotes.