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RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex

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posted on 2023-06-06, 09:40 authored by Fabrizio Martino, Mohinder Pal, Hugo Muñoz-Hernández, Carlos F Rodríguez, Rafael Núñez-Ramírez, David Gil-Carton, Gianluca Degliesposti, J Mark Skehel, S Mark Roe, Chrisostomos Prodromou, Laurence H Pearl, Oscar Llorca
The R2TP/Prefoldin-like co-chaperone, in concert with HSP90, facilitates assembly and cellular stability of RNA polymerase II, and complexes of PI3-kinase-like kinases such as mTOR. However, the mechanism by which this occurs is poorly understood. Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1–RUVBL2–RPAP3–PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. A 3.6?Å cryo-EM structure reveals direct interaction of a C-terminal domain of RPAP3 and the ATPase domain of RUVBL2, necessary for human R2TP assembly but absent from yeast. The mobile TPR domains of RPAP3 map to the opposite face of the ring, associating with PIH1D1, which mediates client protein recruitment. Thus, RPAP3 provides a flexible platform for bringing HSP90 into proximity with diverse client proteins.

Funding

Award Enhancement Grant; Wellcome Trust; 095605/Z/11/A

Mechanisms of client protein recognition and activation by the HSP90 molecular chaperone; Wellcome Trust; 095605/Z/11/Z

History

Publication status

  • Published

File Version

  • Published version

Journal

Nature Communications

ISSN

2041-1723

Publisher

Nature Publishing Group

Issue

1

Volume

9

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-04-16

First Open Access (FOA) Date

2018-04-16

First Compliant Deposit (FCD) Date

2018-04-16

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