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TitleStructure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex.
Journal, issue, pagesCell, Year 2026
Publish dateJan 8, 2026
AuthorsChristopher J Lupton / Charles Bayly-Jones / Shuqi Dong / Terrance Lam / Wentong Luo / Gareth D Jones / Chantel Mastos / Nicholas J Frescher / San S Lim / Alastair C Keen / Luke E Formosa / Hari Venugopal / Yong-Gang Chang / Michelle L Halls / Andrew M Ellisdon /
PubMed AbstractThe guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome ...The guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome downstream of amino acid fluctuations. Under low amino acid conditions, GTPase-activating protein (GAP) activity toward Rags 1 (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.
External linksCell / PubMed:41512879
MethodsEM (single particle)
Resolution3.34 - 5.0 Å
Structure data

EMDB-70140, PDB-9o5d:
The KICSTOR-GATOR1-SAMTOR complex
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-70141, PDB-9o5e:
The dimeric KICSTOR-GATOR1 supercomplex
Method: EM (single particle) / Resolution: 5.0 Å

Source
  • homo sapiens (human)
KeywordsCELL CYCLE / Lysosome / GATOR1 / KICSTOR / cell growth / amino acid sensing / mTOR / KPTN / ITFG2 / C12orf66 / SZT2 / NPRL2 / NPRL3 / DEPDC5

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