The Distinct Assignments for Hsp90α and Hsp90β: More Than Skin Deep

For decades, the undisputable definition of the cytosolic Hsp90 alpha and hsp90 beta proteins being evolutionarily conserved, ATP-driven chaperones has ruled basic research and clinical trials. The results of recent studies, however, have fundamentally challenged this paradigm, not to mention the spectacular failures of the paradigm-based clinical trials in cancer and beyond. We now know that Hsp90 alpha and Hsp90 beta are both ubiquitously expressed in all cell types but assigned for distinct and irreplaceable functions. Hsp90 beta is essential during mouse development and Hsp90 alpha only maintains male reproductivity in adult mice. Neither Hsp90 beta nor Hsp90 alpha could substitute each other under these biological processes. Hsp90 beta alone maintains cell survival in culture and Hsp90 alpha cannot substitute it. Hsp90 alpha also has extracellular functions under stress and Hsp90 beta does not. The dramatic difference in the steady-state expression of Hsp90 in different mouse organs is due to the variable expressions of Hsp90 alpha. The lowest expression of Hsp90 is less than 2% and the highest expression of Hsp90 is 9% among non-transformed cell lines. The two linker regions only take up less than 5% of the Hsp90 proteins, but harbor 21% of the total amino acid substitutions, i.e., 40% in comparison to the 86% overall amino acid homology. A full understanding of the distinctions between Hsp90 alpha and Hsp90 beta could lead to new, safe and effective therapeutics targeting Hsp90 in human disorders such as cancer. This is the first comprehensive review of a comparison between the two cytosolic Hsp90 isoforms.