Investigating the Specificity of Coiled Coil Recognition

Abstract

bZIP transcription factors make up a family of long α-helical proteins that dimerize and bind to DNA through a basic region that contains hydrophobic residues. They function as gene expression regulating factors and are therefore attractive possible candidates for small molecule binding. Binding specificity is a particular topic of interest. The development of an accurate method to characterize and map out the binding specificity of these bZIP proteins, would enable us to alter and possibly inhibit the function of its protein interactions. Use of the Knob-Socket model for determination of packing structure provides a novel approach to analyze protein-protein as well as protein-nucleic acid interactions. A Knob-Socket analysis of the protein-protein interface provides unique insight into the classical leucine zipper pseudo-7mer repeat. A deeper analysis of longer leucine zippers shows unique packing patterns not indicated by classical representations like the helical wheel. From analysis of the Knob-Socket packing maps, this research provides evidence of a general framework for defining the specificity between coiled coils. the Knob-Socket maps show how hydrophobic specificity is defined in the coiled coil interface, where knobs are centralized in the middle of the socket packing, while the peripheral socket residues are hydrophilic. Furthermore, the bias of the filled over free propensities shows a clear pattern that explains the specificity of a set of hydrophobic interactions