HSP90 at the hub of protein homeostasis: emerging mechanistic insights

Heat shock protein 90 (HSP90) is an abundant and evolutionarily highly conserved molecular chaperone that regulates the maturation, activity and stability of a wide range of substrate proteins (clients). In eukaryotes, HSP90 is essential for survival during heat and other stresses, but it also has a central role in a vast array of signal transduction pathways in non-stressful conditions.HSP90 exists as a dimer that undergoes ATP-dependent conformational changes during client protein maturation (known as the chaperone cycle). How the chaperone cycle is mechanistically connected to client protein folding is just beginning to be understood. The extreme conformation flexibility of HSP90 sets it apart from other chaperone systems and renders its study remarkably complex.More than 20 known co-chaperones regulate HSP90 function in many different ways. Some co-chaperones modulate HSP90 ATPase activity and the chaperone cycle, and others seem to function as adaptors that recruit specific client proteins. Post-translational modifications of HSP90 and co-chaperones add further regulatory layers.The best-characterized HSP90 client proteins are kinases and steroid hormone receptors. However, recent studies have uncovered numerous genes and proteins that either physically or genetically interact with HSP90. In yeast, Hsp90 is functionally linked to ∼20% of all genes. HSP90 has been implicated in RNA processing, membrane trafficking and in innate and adaptive immunity.Despite the numerous client proteins, clear structural or sequence determinants for HSP90 binding remain largely unknown. Client protein recognition is one of the largest puzzles in the field.