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Regulation of human mTOR complexes by DEPTOR.
Matthias Wälchli1, Karolin Berneiser1, Francesca Mangia1
1Biozentrum, University of Basel, Basel, Switzerland.
Elife
|September 14, 2021
Summary
The DEP domain-containing mTOR interacting protein (DEPTOR) regulates both mTOR complexes. Its structured regions bind mTOR, influencing cell growth, metabolism, and cancer, offering new therapeutic targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- DEPTOR is a vertebrate-specific protein regulating both mTORC1 and mTORC2.
- DEPTOR plays critical roles in metabolism, immunity, and cancer, acting as an oncoprotein or tumor suppressor.
- mTOR (mammalian target of rapamycin) is a central regulator of cell growth.
Purpose of the Study:
- To elucidate the structural basis of DEPTOR interaction with mTORC1 and mTORC2.
- To understand how DEPTOR binding regulates mTOR activity.
- To explore the implications for DEPTOR's roles in physiology and disease.
Main Methods:
- Biochemical analysis of DEPTOR-mTOR complexes.
- Cryo-electron microscopy (cryo-EM) reconstructions.
- Structural analysis of DEPTOR domains (PDZ and DEPt) interacting with mTOR.
Main Results:
- Both PDZ and DEPt domains of DEPTOR are crucial for mTOR interaction.
- The PDZ domain binds mTOR, while the DEPt domain allosterically suppresses activation.
- DEPTOR can also be phosphorylated by mTOR in a substrate-like manner, inhibiting basal mTOR activity.
- Binding interfaces allow for regulation by other signaling pathways.
Conclusions:
- The multifaceted DEPTOR-mTOR interaction mechanism explains DEPTOR's diverse physiological roles.
- Understanding these interactions opens avenues for targeting the mTOR-DEPTOR axis in diseases like cancer.
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