Molecular-level interplay between intrinsically disordered clients and Hsp90

Proteostasis is maintained by a network of molecular chaper-ones, a prominent member of which is the 90-kilodalton heat shock protein Hsp90. The chaperone function of Hsp90 has been extensively reviewed previously, emphasizing its ATPase activity and remodeling of folded client proteins. Experimental evidence implicating Hsp90 in neurodegenerative diseases has bolstered interest in the noncanonical chaperoning of intrinsically disordered protein (IDPs), however the interplay between Hsp90 and its disordered clients remains poorly un-derstood. In this review we describe recent advances that have contributed to our understanding of the intricate mechanisms characterizing Hsp90-mediated chaperoning of the IDPs tau and a-synuclein and survey emerging insights into the modu-lation of the chaperone-client interplay in the context of neurodegeneration.

Automated summary

Proteostasis is maintained by a network of molecular chaperones, with Hsp90 being a prominent member. While the chaperone function of Hsp90 has been extensively studied, its interaction with intrinsically disordered proteins (IDPs) remains poorly understood. This review highlights recent advances in understanding the mechanisms of Hsp90-mediated chaperoning of IDPs, focusing on tau and α-synuclein, and provides insights into the modulation of chaperone-client interaction in neurodegenerative diseases.