Protein design to understand peptide ligand recognition by tetratricopeptide repeat proteins

Abstract

Protein design aims to understand the fundamentals of protein structure by creating novel proteins with prespecified folds. An equally important goal is to understand protein function by creating novel proteins with prespecified activities. Here we describe the design and characterization of a tetratricopeptide (TPR) protein, which binds to the C-terminal peptide of the eukaryotic chaperone Hsp90. The design emphasizes the importance of both direct, short-range protein-peptide interactions and of long-range electrostatic optimization. We demonstrate that the designed protein binds specifically to the desired peptide and discriminates between it and the similar C-terminal peptide of Hsp70.