RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex.
View/ Open
Date
2018-04-16ICR Author
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
Metadata
Show full item recordAbstract
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.
Collections
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 - ?
Publisher
Springer Science and Business Media LLC
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
Related items
Showing items related by title, author, creator and subject.
-
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint.
Bigot, N; Day, M; Baldock, RA; Watts, FZ; Oliver, AW; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2019-05-28)Coordination of the cellular response to DNA damage is organised by multi-domain 'scaffold' proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ... -
Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.
Xiong, S; Lorenzen, K; Couzens, AL; Templeton, CM; Rajendran, D; et al. (CELL PRESS, 2018-08-07)The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase ... -
Multiparametric Analysis of Cell Shape Demonstrates that β-PIX Directly Couples YAP Activation to Extracellular Matrix Adhesion.
Sero, JE; Bakal, C (CELL PRESS, 2017-01-25)Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control ...