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Regulation of human mTOR complexes by DEPTOR
Matthias Wälchli1, Karolin Berneiser1, Francesca Mangia1
1Biozentrum, University of Basel, Basel, Switzerland.
Abstract:
The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.
Insights
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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