Identification of “exosite” contacts in TRAF6, a critical mediator of cancer

Massachusetts Institute Of Technology, Cambridge MA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Many diseases are caused not by outside pathogens, but by misregulation of proteins that otherwise maintain homeostasis or suppress disease. Successful treatments for human cancers rely on our ability to disrupt protein-protein interactions (PPIs) that drive tumorigenicity, angiogenesis, and metastasis. Unfortunately, several challenges make designing PPI inhibitors a difficult task. A major impediment is designing inhibitors that bind tightly and specifically to the target receptor. Studies that define a binding motif for a protein domain are often limited by knowledge of only a few ligands. Additionally, it is common to study only those parts of ligands that form contacts observed in high-resolution x-ray studies. This proposal will comprehensively examine ligand sequence space both at the core interaction site and at peripheral regions that could interact with distal sites on the receptor surface, here termed exosites. This groundwork will then permit design of peptide inhibitors that not only optimize the known binding site, but seek to expand it to introduce tighter, more specific contacts. For this project, I have chosen to target TNF? Receptor Associated Factor 6 (TRAF6). TRAF6 participates in several cancer pathways, where it is either misregulated or overexpressed. My specific aims will: 1) characterize the binding preferences of TRAF6 in the ligand pocket, 2) test for exosite contacts within 8 residues of the binding sequence at either terminus, and 3) combine the knowledge gained to test optimized peptides for affinity and specificity for TRAF6 over other TRAF family members. Successful completion of this project will provide specific, high-affinity peptide PPI inhibitors against TRAF and a general workflow that could be applied to other peptide design projects, particularly those where the designable sites are limited by small interfaces.