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Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone

DOI: 10.1016/j.celrep.2021.109317 DOI Help

Authors: Mohinder Pal (University of Sussex) , Hugo Munoz-Hernandez (Spanish National Cancer Research Centre (CNIO)) , Dennis Bjorklund (University of Sussex) , Lihong Zhou (University of Sussex) , Gianluca Degliesposti (MRC Laboratory of Molecular Biology) , J. Mark Skehel (MRC Laboratory of Molecular Biology) , Emma L. Hesketh (University of Leeds) , Rebecca F. Thompson (University of Leeds) , Laurence H. Pearl (University of Sussex; Institute of Cancer Research, Chester Beatty Laboratories) , Oscar Llorca (Spanish National Cancer Research Centre (CNIO)) , Chrisostomos Prodromou (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 36

State: Published (Approved)
Published: July 2021

Open Access Open Access

Abstract: The R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) complex, in collaboration with heat shock protein 90 (HSP90), functions as a chaperone for the assembly and stability of protein complexes, including RNA polymerases, small nuclear ribonucleoprotein particles (snRNPs), and phosphatidylinositol 3-kinase (PI3K)-like kinases (PIKKs) such as TOR and SMG1. PIKK stabilization depends on an additional complex of TELO2, TTI1, and TTI2 (TTT), whose structure and function are poorly understood. The cryoelectron microscopy (cryo-EM) structure of the human R2TP-TTT complex, together with biochemical experiments, reveals the mechanism of TOR recruitment to the R2TP-TTT chaperone. The HEAT-repeat TTT complex binds the kinase domain of TOR, without blocking its activity, and delivers TOR to the R2TP chaperone. In addition, TTT regulates the R2TP chaperone by inhibiting RUVBL1-RUVBL2 ATPase activity and by modulating the conformation and interactions of the PIH1D1 and RPAP3 components of R2TP. Taken together, our results show how TTT couples the recruitment of TOR to R2TP with the regulation of this chaperone system.

Journal Keywords: R2TP; TTT; TELO2; TTI1; TTI2; RUVBL1; RUVBL2; HSP90 chaperone; mTOR; PIKK

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 21/07/2021 13:16


Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)