Intrinsic Helicity of Disordered Basic Regions of Bzip Transcription Factors: Implications For Mechanisms of DNA Binding

Abstract

Transcription factors (TFs) are enriched in disorder promoting residues. Basic leucine zipper (bZip) TFs comprises of a basic DNA binding region (bR) and a leucine zipper region (LZ). It is believed that bZip monomers are intrinsically disordered; this is especially true of the bRs. Folding of bZips is assumed to be coupled to DNA binding. The mechanism of conformational change coupled to DNA binding remains unresolved. Here, we report results from a systematic computational and experimental studies to scrutinize the role of bRs of the bZip TFs in DNA binding. Our results show that bR sequences encode varying extents of helicity that are confirmed by comparing simulation results to UV-CD measurements. Partial helicity in bRs derives from intrinsic helicity for the consensus 10-residue stretch, which we refer to as DNA binding signature sequences (bRSS). This element or aMoRE is flanked by N-terminal acidic groups and C-terminal basic groups, which act as helix capping boxes and the overall helicity within bR is modulated by the nature of these charged caps. Furthermore, our simulation results revealed that the overall helicity of the bZIP show strong positive correlation with the helicity of the bR and weak positive correlation with the helicity in LZ while the helicities in bR and LZ are also weakly correlated. These findings lead us to propose a phenomenological model for DNA binding of bZip. DNA binding can occur via at least two parallel channels, and the proposal is that flux through the two channels is controlled by both the intrinsic helicity in the BR and the stability of the dimer formed by LZ of bZips.