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

DOI: 10.1038/s41467-018-03942-1 DOI Help

Authors: Fabrizio Martino (Centro de Investigaciones Biológicas (CIB), Spanish National Research Council (CSIC)) , Mohinder Pal (University of Sussex) , Hugo Muñoz-Hernández (Spanish National Cancer Research Centre (CNIO)) , Carlos F. Rodríguez (Spanish National Cancer Research Centre (CNIO)) , Rafael Núñez-Ramírez (Centro de Investigaciones Biológicas (CIB), Spanish National Research Council (CSIC)) , David Gil-Carton (CIC bioGUNE) , Gianluca Degliesposti (MRC Laboratory of Molecular Biology) , J. Mark Skehel (MRC Laboratory of Molecular Biology) , Mark Roe (University of Sussex) , Chrisostomos Prodromou (University of Sussex) , Laurence H. Pearl (University of Sussex) , Oscar Llorca (Spanish National Cancer Research Centre (CNIO))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: April 2018
Diamond Proposal Number(s): 13312 , 13520 , 15997

Open Access Open Access

Abstract: 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.

Journal Keywords: Biochemistry; Cryoelectron microscopy; Structural biology

Subject Areas: Biology and Bio-materials, Chemistry

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 16/04/2018 12:03


Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)