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Instruments / Technical Area	Publication Details	Published
Krios I-Titan Krios I at Diamond	RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex Fabrizio Martino , Mohinder Pal , Hugo Muñoz-hernández , Carlos F. Rodríguez , Rafael Núñez-ramírez , David Gil-carton , Gianluca Degliesposti , J. Mark Skehel , Mark Roe , Chrisostomos Prodromou , Laurence H. Pearl , Oscar Llorca Nature Communications 9 DOI: 10.1038/s41467-018-03942-1 Diamond Proposal Number(s): [13312, 13520, 15997] Open Access Show Abstract ▼ 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.	Apr 2018
Krios I-Titan Krios I at Diamond	The Structure of the R2TP Complex Defines a Platform for Recruiting Diverse Client Proteins to the HSP90 Molecular Chaperone System Angel Rivera-calzada , Mohinder Pal , Hugo Muñoz-hernández , Juan R. Luque-ortega , David Gil-carton , Gianluca Degliesposti , J. Mark Skehel , Chrisostomos Prodromou , Laurence H. Pearl , Oscar Llorca Structure 25, 1145 - 1152.e4 DOI: 10.1016/j.str.2017.05.016 Diamond Proposal Number(s): [13520, 14507] Open Access Show Abstract ▼ Abstract: The R2TP complex, comprising the Rvb1p-Rvb2p AAA-ATPases, Tah1p, and Pih1p in yeast, is a specialized Hsp90 co-chaperone required for the assembly and maturation of multi-subunit complexes. These include the small nucleolar ribonucleoproteins, RNA polymerase II, and complexes containing phosphatidylinositol-3-kinase-like kinases. The structure and stoichiometry of yeast R2TP and how it couples to Hsp90 are currently unknown. Here, we determine the 3D organization of yeast R2TP using sedimentation velocity analysis and cryo-electron microscopy. The 359-kDa complex comprises one Rvb1p/Rvb2p hetero-hexamer with domains II (DIIs) forming an open basket that accommodates a single copy of Tah1p-Pih1p. Tah1p-Pih1p binding to multiple DII domains regulates Rvb1p/Rvb2p ATPase activity. Using domain dissection and cross-linking mass spectrometry, we identified a unique region of Pih1p that is essential for interaction with Rvb1p/Rvb2p. These data provide a structural basis for understanding how R2TP couples an Hsp90 dimer to a diverse set of client proteins and complexes.	Jul 2017
I24-Microfocus Macromolecular Crystallography	Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. Shuo Chen , Doryen Bubeck , Bryan T Macdonald , Wen-xue Liang , Jian-hua Mao , Tomas Malinauskas , Oscar Llorca , Alexandru Aricescu , Christian Siebold , Xi He , Edith Jones Developmental Cell 21, 848 - 861 DOI: 10.1016/j.devcel.2011.09.007 PMID: 3564486 Show Abstract ▼ Abstract: LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller–EGF-like domain (PE) pairs which harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites.	Dec 2011

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