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Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9.
- Source :
-
Nature structural & molecular biology [Nat Struct Mol Biol] 2020 Nov; Vol. 27 (11), pp. 1017-1023. Date of Electronic Publication: 2020 Aug 31. - Publication Year :
- 2020
-
Abstract
- The Rag GTPases (Rags) recruit mTORC1 to the lysosomal membrane in response to nutrients, where it is then activated in response to energy and growth factor availability. The lysosomal folliculin (FLCN) complex (LFC) consists of the inactive Rag dimer, the pentameric scaffold Ragulator, and the FLCN:FNIP2 (FLCN-interacting protein 2) GTPase activating protein (GAP) complex, and prevents Rag dimer activation during amino acid starvation. How the LFC is disassembled upon amino acid refeeding is an outstanding question. Here we show that the cytoplasmic tail of the human lysosomal solute carrier family 38 member 9 (SLC38A9) destabilizes the LFC and thereby triggers GAP activity of FLCN:FNIP2 toward RagC. We present the cryo-EM structures of Rags in complex with their lysosomal anchor complex Ragulator and the cytoplasmic tail of SLC38A9 in the pre- and post-GTP hydrolysis state of RagC, which explain how SLC38A9 destabilizes the LFC and so promotes Rag dimer activation.
- Subjects :
- Amino Acid Transport Systems chemistry
Amino Acid Transport Systems ultrastructure
Cryoelectron Microscopy
HEK293 Cells
Humans
Hydrolysis
Models, Molecular
Monomeric GTP-Binding Proteins chemistry
Monomeric GTP-Binding Proteins ultrastructure
Protein Conformation
Protein Multimerization
Amino Acid Transport Systems metabolism
Guanosine Triphosphate metabolism
Monomeric GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1545-9985
- Volume :
- 27
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nature structural & molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 32868926
- Full Text :
- https://doi.org/10.1038/s41594-020-0490-9