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Nat Commun. 2019 Jun 28;10(1):2865. doi: 10.1038/s41467-019-10781-1.

Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly.

Author information

1
Centro Nacional de Biotecnología, Campus de la Universidad Autónoma de Madrid, 28049, Madrid, Spain.
2
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA.
3
Department of Internal Medicine, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, 84112, USA.
4
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA. bmwillardson@chem.byu.edu.
5
Centro Nacional de Biotecnología, Campus de la Universidad Autónoma de Madrid, 28049, Madrid, Spain. jmv@cnb.csic.es.

Abstract

The mechanistic target of rapamycin (mTOR) kinase forms two multi-protein signaling complexes, mTORC1 and mTORC2, which are master regulators of cell growth, metabolism, survival and autophagy. Two of the subunits of these complexes are mLST8 and Raptor, β-propeller proteins that stabilize the mTOR kinase and recruit substrates, respectively. Here we report that the eukaryotic chaperonin CCT plays a key role in mTORC assembly and signaling by folding both mLST8 and Raptor. A high resolution (4.0 Å) cryo-EM structure of the human mLST8-CCT intermediate isolated directly from cells shows mLST8 in a near-native state bound to CCT deep within the folding chamber between the two CCT rings, and interacting mainly with the disordered N- and C-termini of specific CCT subunits of both rings. These findings describe a unique function of CCT in mTORC assembly and a distinct binding site in CCT for mLST8, far from those found for similar β-propeller proteins.

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