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Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly.
- Source :
-
Nature communications [Nat Commun] 2019 Jun 28; Vol. 10 (1), pp. 2865. Date of Electronic Publication: 2019 Jun 28. - Publication Year :
- 2019
-
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.
- Subjects :
- Amino Acid Sequence
Binding Sites
Cryoelectron Microscopy
Gene Expression Regulation physiology
Gene Knockdown Techniques
HEK293 Cells
Hep G2 Cells
Humans
Mass Spectrometry
Models, Molecular
Protein Binding
Protein Conformation
Protein Folding
Regulatory-Associated Protein of mTOR genetics
TOR Serine-Threonine Kinases genetics
mTOR Associated Protein, LST8 Homolog genetics
Chaperonin Containing TCP-1 physiology
Regulatory-Associated Protein of mTOR metabolism
TOR Serine-Threonine Kinases metabolism
mTOR Associated Protein, LST8 Homolog metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31253771
- Full Text :
- https://doi.org/10.1038/s41467-019-10781-1