Research Article

Architecture of human Rag GTPase heterodimers and their complex with mTORC1

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Science  11 Oct 2019:
Vol. 366, Issue 6462, pp. 203-210
DOI: 10.1126/science.aax3939

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Mastering regulation

The mechanistic target of rapamycin complex 1 (mTORC1) is known as the master kinase, acknowledging its key role in integrating multiple signals to regulate cell growth. When nutrients are abundant, heterodimers of Rag, a class of small guanosine triphosphatase, bind to mTORC1 and recruit it to the lysosome. Here, other signaling pathways converge on the mTORC1 complex. Anandapadamanaban et al. determined cryo–electron microscopy and crystal structures of a RagA/RagC heterodimer. The structures, together with dynamic studies, explain the nucleotide states required for binding to mTORC1 and support a mechanism for conformational communication between the RagA and RagC subunits in the heterodimer. RagA/RagC binding causes no conformational change in mTORC1, which is consistent with the idea that mTORC1 must sense additional growth regulators before it is activated.

Science, this issue p. 203

Abstract

The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo–electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.

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