Abstract
In the eukaryotic cytosol, the Hsp70 and the Hsp90 chaperone machines work in tandem with the maturation of a diverse array of client proteins. The transfer of nonnative clients between these systems is essential to the chaperoning process, but how it is regulated is still not clear. We discovered that NudC is an essential transfer factor with an unprecedented mode of action: NudC interacts with Hsp40 in Hsp40-Hsp70-client complexes and displaces Hsp70. Then, the interaction of NudC with Hsp90 allows the direct transfer of Hsp40-bound clients to Hsp90 for further processing. Consistent with this mechanism, NudC increases client activation invitro as well as in cells and is essential for cellular viability. Together, our results show the complexity of the cooperation between the major chaperone machineries in the eukaryotic cytosol.
Highlights
Molecular chaperones have evolved to support the correct folding and maturation of proteins, called clients, into their native, active conformation, and to prevent deleterious misfolding and aggregation (Balchin et al, 2016)
The interaction of NudC with heat shock protein 90 (Hsp90) allows the direct transfer of Hsp40-bound clients to Hsp90 for further processing
We unravel that NudC is a functionally and structurally unique co-chaperone that directly interacts with Hsp40 and Hsp90 using independent binding sites. We show that it accelerates the client transfer from Hsp40/heat shock protein 70 (Hsp70) to Hsp90 by an unprecedented mechanism
Summary
Molecular chaperones have evolved to support the correct folding and maturation of proteins, called clients, into their native, active conformation, and to prevent deleterious misfolding and aggregation (Balchin et al, 2016). Hsp and the associated Hsp40/Jdomain protein (JDP) co-chaperones (hereafter referred to as Hsp40) unfold proteins in an ATP-dependent manner. Together, they play a pivotal role in facilitating the de novo folding of proteins, preventing protein aggregation and re-solubilizing aggregated proteins (Faust et al, 2020; Mayer and Bukau, 2005; Rosenzweig et al, 2019; Wentink et al, 2020). Hsp binds to clients more promiscuously than Hsp, which is predominantly involved in the late stages of maturation
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