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

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Publication Date
2018-04-16
ICR Author
Pearl, Laurence
Author
Martino, F
Pal, M
Muñoz-Hernández, H
Rodríguez, CF
Núñez-Ramírez, R
Gil-Carton, D
Degliesposti, G
Skehel, JM
Roe, SM
Prodromou, C
Pearl, LH
Llorca, O
Type
Journal Article
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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.
URL
https://repository.icr.ac.uk/handle/internal/3735
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  • Other ICR Research
Licenseref URL
https://creativecommons.org/licenses/by/4.0
Version of record
10.1038/s41467-018-03942-1
Subject
Animals
Humans
Escherichia coli
Saccharomyces cerevisiae
DNA Helicases
Carrier Proteins
Molecular Chaperones
Recombinant Proteins
Cryoelectron Microscopy
Cloning, Molecular
Gene Expression
Binding Sites
Amino Acid Sequence
Protein Binding
Genetic Vectors
Models, Molecular
HSP90 Heat-Shock Proteins
Apoptosis Regulatory Proteins
Protein Interaction Domains and Motifs
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
ATPases Associated with Diverse Cellular Activities
Language
eng
Date accepted
2018-03-21
License start date
2018-04-16
Citation
Nature communications, 2018, 9 (1), pp. 1501 - ?

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