Abstract
Structures of components of cancer-associated mTORC1 bound to regulators reveal mechanisms.
Major Finding: Structures of components of cancer-associated mTORC1 bound to regulators reveal mechanisms.
Mechanism: Rag heterodimers interact with mTORC1 component RAPTOR to localize mTORC1 to lysosomal membranes.
Impact: These structures will enable basic and translational studies, possibly including drug development.
The serine/threonine protein-kinase complex mTORC1 is a major regulator of cellular and organismal growth, and its deregulation is associated with several cancers. Small GTPases called Rags, which form heterodimers, are required for mTORC1 activation, but much about how they interact with mTORC1 is unknown. To investigate this, Anandapadamanaban and colleagues used cryo-electron microscopy (cryo-EM) and X-ray crystallography to determine the structures of mTORC1 bound to RagA–RagC heterodimers and RagA–RagC heterodimers alone. Binding to RagA–RagC did not cause a conformational change in mTORC1, implying that the function of Rag-heterodimer binding may be to localize mTORC1 to the lysosomal surface (where mTORC1 can be activated) through the Rags' interaction with the Ragulator complex. Combining these results with those of previous structural studies suggests that mTORC1 can associate with the required activator RHEB on the lysosomal surface while keeping the mTOR active sites facing the cytosol, allowing mTOR to phosphorylate its cytosolic targets. In a separate study, Rogala and colleagues used cryo-EM to determine the structure of mTORC1′s RAPTOR subunit bound to the Rag–Ragulator complex. This structure supports a model in which transient interactions between RAPTOR and GTP-bound RagA along with weak interactions between RAPTOR and RagC together promote a stronger interaction between RAPTOR and the Rag heterodimer only once RagC is bound to GDP. Knowledge of this structure along with the results of prior structural studies enabled modeling of mTORC1 docked on the lysosomal surface. Further, the characterization of the interface between RAPTOR and the RagA–RagC heterodimer provides insight that may be valuable in developing small molecules targeting mTORC1 signaling with greater specificity than that of currently available drugs. Together, these two structural studies have led to a much more detailed understanding of mTORC1 regulation than was previously available, providing a basis for continued work on this important complex.
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