Structural determinants of coiled-coil affinity in a cancer regulator

Coiled-coils are the simplest example of a structure made from two separate protein chains. They are involved in a wide range of interactions both inside and outside the cell. Our studies will focus on the Jun-Fos system, which contains a repetitive and yet highly specific coiled coil motif that is responsible for mediating dimerisation. The Jun-Fos system forms the heterodimeric transcription factor Activator Protein-1 (AP-1), which plays a key role in many types of cancer. It is known that particular members of the Jun and Fos families are deregulated or overexpressed in tumorigenic phenotypes. AP-1 represents a legitimate therapeutic target since it is found at the end of several cell signalling cascades. To probe how specific protein-protein interactions are achieved, we designed peptides that bind with high affinity for cFos or cJun. While we now have a good thermodynamics understanding of how these antagonists achieve stable interaction with their target, we aim to obtain high-resolution structures and quantify the dynamics in the coiled-coil, to understand the molecular basis of stability and specificity at the atomic level.

Entry requirements: the standard minumum entry requirement is 2:1 in Chemistry, Physics, Biochemistry or related subjects