Hsp90 as a Member of Dicarboxylate Clamp TPR Protein Interaction Network: Implication in Human Diseases and Prospect as a Drug Target

Abstract

Heat shock protein (Hsp) 90 kDa is a widely expressed molecular chaperone and is involved in folding of broad range of client proteins, intracellular transport and degradation of damaged and misfolded proteins. The function of Hsp90 is mediated through its partner co-chaperones, which either affects the ATPase activity or directly helps Hsp90 to interact with its specific client proteins. Tetratricopeptide repeat (TPR) domain containing proteins represent a major class of co-chaperones which interact with the extreme C-terminus of Hsp90 through a dicarboxylate clamp mechanism. We have recently suggested that Hsp90 and Hsp70 molecular chaperones belong to dicarboxylate clamp protein interaction network where proteins containing similar C-terminus as that of Hsp90/Hsp70 interact with TPR motif containing proteins through dicarboxylate clamp mechanism. Recent findings suggest that several of TPR co-chaperones have been involved in variety of human diseases such as tauopathy and amyloidopathy in Alzheimer’s disease, cancer, metabolic disorders, inflammation and others. In this chapter, we discuss the potential of Hsp90 TPR containing co-chaperones as drug targets in human disorders.