![]() ![]() Cdc37 inhibits Hsp90's ATPase activity and is therefore thought to promote assembly of the misfolded kinase into a multichaperone complex. Another important co-chaperone Cdc37 (cell-division cycle 37), which interacts with both protein kinases and Hsp90, and, because it is essential for protein kinase maturation, is therefore known as a ‘kinase co-chaperone’. The connection of and the interplay between the two chaperones are crucial for cell viability. For example, Hsp70 and Hsp90 form a multichaperone complex in which both are connected by a co-chaperone called HOP (Hsp70/90-organizing protein). Previous reports showed that several co-chaperones interact with Hsp90 in a sequential manner to assemble functional chaperone machinery. Furthermore, conformational changes associated with ATP binding and hydrolysis are accompanied with the binding and release of a distinct set of co-chaperones. Exhaustive analyses, together with crystal structures of Hsp90, have revealed that ATP binding and hydrolysis lead to a series of conformational rearrangements which trigger the chaperone cycle of Hsp90. Although the Hsp90 chaperone machinery can be regulated by these three mechanisms, whether or not there is a fourth mechanism is still unknown. The chaperone function of Hsp90 is modulated at three major levels, its intrinsic ATPase activity, the association with distinct conformation-specific co-chaperones and post-translational modifications. Further investigation demonstrated that the reciprocal regulation of Hsp90α and PKCγ plays a critical role in cancer cells, and that simultaneous inhibition of PKCγ and Hsp90α synergistically prevents cell migration and promotes apoptosis in cancer cells. Moreover, phosphorylation of Hsp90α by PKCγ decreases the binding affinity of Hsp90α towards ATP and co-chaperones such as Cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. A threonine residue set, Thr 115/Thr 425/Thr 603, of Hsp90α is specifically phosphorylated by PKCγ, and, more interestingly, this threonine residue set serves as a ‘phosphorylation switch’ for Hsp90α binding or release of PKCγ. First, we prove that PKCγ (protein kinase Cγ) is a client protein of Hsp90α, and, that by interacting with PKCγ, Hsp90α prevents PKCγ degradation and facilitates its cytosol-to-membrane translocation and activation. The present study is the first example to show that a client kinase directly regulates Hsp90 activity, which is a novel level of regulation for the Hsp90 chaperone machinery. However, it is unclear whether client proteins themselves participate in regulation of the chaperoning process. It is believed that the stability and activity of client proteins are passively regulated by the Hsp90 (heat-shock protein 90) chaperone machinery, which is known to be modulated by its intrinsic ATPase activity, co-chaperones and post-translational modifications. ![]() Access content during the Covid-19 pandemic. ![]()
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