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

Author

Listed:
  • Fabrizio Martino

    (Spanish National Research Council (CSIC))

  • Mohinder Pal

    (School of Life Sciences, University of Sussex, Falmer)

  • Hugo Muñoz-Hernández

    (Spanish National Research Council (CSIC)
    Spanish National Cancer Research Centre (CNIO))

  • Carlos F. Rodríguez

    (Spanish National Research Council (CSIC)
    Spanish National Cancer Research Centre (CNIO))

  • Rafael Núñez-Ramírez

    (Spanish National Research Council (CSIC))

  • David Gil-Carton

    (CIC bioGUNE, Bizkaia Technology Park)

  • Gianluca Degliesposti

    (Cambridge Biomedical Campus)

  • J. Mark Skehel

    (Cambridge Biomedical Campus)

  • S. Mark Roe

    (School of Life Sciences, University of Sussex, Falmer)

  • Chrisostomos Prodromou

    (School of Life Sciences, University of Sussex, Falmer)

  • Laurence H. Pearl

    (School of Life Sciences, University of Sussex, Falmer)

  • Oscar Llorca

    (Spanish National Research Council (CSIC)
    Spanish National Cancer Research Centre (CNIO))

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.

Suggested Citation

  • 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 &, 2018. "RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03942-1
    DOI: 10.1038/s41467-018-03942-1
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