Martino, Fabrizio, Pal, Mohinder, Muñoz-Hernández, Hugo, Rodríguez, Carlos F, Núñez-Ramírez, Rafael, Gil-Carton, David, Degliesposti, Gianluca, Skehel, J Mark, Roe, S Mark, Prodromou, Chrisostomos, Pearl, Laurence H and Llorca, Oscar (2018) RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex. Nature Communications, 9 (1). ISSN 2041-1723

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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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Biochemistry School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups:	Genome Damage and Stability Centre
Subjects:	Q Science > QP Physiology > QP0501 Animal biochemistry Q Science > QP Physiology > QP0501 Animal biochemistry > QP0551 Proteins, amino acids, etc.
Depositing User:	Laurence Pearl
Date Deposited:	16 Apr 2018 14:43
Last Modified:	01 May 2018 15:39
URI:	http://srodev.sussex.ac.uk/id/eprint/75133

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