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Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM
journal contribution
posted on 2023-06-09, 17:44 authored by Hugo Muñoz-Hernández, Mohinder Pal, Carlos F Rodríguez, Rafael Fernandez-Leiro, Chrisostomos ProdromouChrisostomos Prodromou, Laurence PearlLaurence Pearl, Oscar LlorcaThe 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.
Funding
Mechanisms of client protein activation and regulation by the Hsp90 molecular chaperone system; G0662; WELLCOME TRUST; 095605/Z/11/Z
Structural basis for TOR activation by the HSP90-R2TP-TTT molecular chaperone complex; BBSRC; BB/R01678X/1
History
Publication status
- Published
File Version
- Published version
Journal
Science AdvancesISSN
2375-2548Publisher
American Association for the Advancement of ScienceExternal DOI
Issue
5Volume
5Page range
1-11Article number
eaaw1616Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-05-08First Open Access (FOA) Date
2019-05-08First Compliant Deposit (FCD) Date
2019-05-07Usage metrics
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