Structure of the lysosomal KICSTOR–GATOR1–SAMTOR nutrient-sensing supercomplex; Lupton, Bayly-Jones et al.
Description
The GTP-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mTORC1 activation at the lysosome downstream of amino acid fluctuations. Under low amino acid conditions, GATOR1 promotes RagA GTP hydrolysis, preventing mTORC1 activation. KICSTOR recruits and regulates GATOR1 at the lysosome by undefined mechanisms. Here, we resolve the KICSTOR–GATOR1 structure, revealing a striking ~60 nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface, and mutations that disrupt this interaction impair mTORC1 regulation. The S-adenosylmethionine sensor SAMTOR binds KICSTOR in a manner incompatible with metabolite binding, providing structural insight into methionine sensing via SAMTOR–KICSTOR association. We discover that KICSTOR and GATOR1 form a dimeric supercomplex. This assembly restricts GATOR1 to an orientation that favors the low-affinity active GAP mode of Rag GTPase engagement while sterically restricting access to the high-affinity inhibitory mode, consistent with a model of an active lysosomal GATOR1 docking complex.
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- National Health and Medical Research CouncilDepartment of Health and Aged CareAustraliaGrant ID: 2036864
- Australian Research CouncilDepartment of Employment and Workplace RelationsAustraliaGrant ID: DE240100992
- National Health and Medical Research CouncilDepartment of Health and Aged CareAustraliaGrant ID: 2010149
- Australian Research CouncilDepartment of Employment and Workplace RelationsAustraliaGrant ID: LE170100016