Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM

Muñoz-Hernández, Hugo, Pal, Mohinder, Rodríguez, Carlos F, Fernandez-Leiro, Rafael, Prodromou, Chrisostomos, Pearl, Laurence H and Llorca, Oscar (2019) Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM. Science Advances, 5 (5). eaaw1616 1-11. ISSN 2375-2548

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Abstract

The human R2TP complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) is an HSP90 co-chaperone required for the maturation of several essential multiprotein complexes, including RNA polymerase II, small nucleolar ribonucleoproteins, and PIKK complexes such as mTORC1 and ATR-ATRIP. RUVBL1-RUVBL2 AAA-ATPases are also primary components of other essential complexes such as INO80 and Tip60 remodelers. Despite recent efforts, the molecular mechanisms regulating RUVBL1-RUVBL2 in these complexes remain elusive. Here, we report cryo-EM structures of R2TP and show how access to the nucleotide-binding site of RUVBL2 is coupled to binding of the client recruitment component of R2TP (PIH1D1) to its DII domain. This interaction induces conformational rearrangements that lead to the destabilization of an N-terminal segment of RUVBL2 that acts as a gatekeeper to nucleotide exchange. This mechanism couples protein-induced motions of the DII domains with accessibility of the nucleotide-binding site in RUVBL1-RUVBL2, and it is likely a general mechanism shared with other RUVBL1-RUVBL2-containing complexes.

Item Type: Article
Keywords: molecular chaperones; multiprotein complexes; cry-electron microscopy
Schools and Departments: 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. > QP0601 Enzymes
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Depositing User: Laurence Pearl
Date Deposited: 08 May 2019 10:27
Last Modified: 01 Jul 2019 15:32
URI: http://sro.sussex.ac.uk/id/eprint/83597

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Project NameSussex Project NumberFunderFunder Ref
Structural basis for TOR activation by the HSP90-R2TP-TTT molecular chaperone complexUnsetBBSRCBB/R01678X/1
Mechanisms of client protein activation and regulation by the Hsp90 molecular chaperone systemG0662WELLCOME TRUST095605/Z/11/Z