Structural characteristics of the TPR Protein-Hsp90 interaction: A new target in biotechnology

Abstract

Nature employs multiple repeat protein scaffolds in order to promote proteinprotein interactions. In this sense, TPR proteins participate in different natural pathways, especially in diverse processes of eukaryotic cells. An important aspect for cellular homeostasis is the folding of newly synthesized peptides to functionally mature proteins, such as SHRs. This process is actively regulated by Hsp70 and Hsp90 with the cooperation of cochaperones. The chaperone Hsp90 is involved in the stabilization of several proteins implicated in signaling, and in the tumor phenotype of various cancers. Cochaperones are a critical component of the cytosolic Hsp90 folding pathway, as their functions include targeting clients to Hsp90 and modulating Hsp90 ATPase activity or conformational changes. The incorrect folding of the protein causes loss of function. This deleterious effect motivates the development of compounds to induce the expression or modulate the function of molecular chaperones. The study of the interaction between proteins and the search for compounds that can modulate the function of chaperones has become extremely important for the advancement of scientific knowledge on different cellular mechanisms and in the searching for new drugs to increase the production of proteins properly folded. A description of diverse structural aspects of Hsp90-TPR cochaperones interaction in the context of SHR, as well as a structural comparison of different isoforms of Hsp90 is presented in this chapter. Besides, the primary and new biotechnological approaches inhibiting Hsp90 interactions are also discussed, since Hsp90 inhibition is a promising new treatment strategy showing clinical activity in specific tumor types.