6WJ2

CryoEM structure of the SLC38A9-RagA-RagC-Ragulator complex in the pre-GAP state

Summary for 6WJ2

• Entry DOI: 10.2210/pdb6wj2/pdb
• Related: 6WJ3
• EMDB information: 21686 21687
• Descriptor: Ragulator complex protein LAMTOR1, 9-{5-O-[(S)-hydroxy{[(R)-hydroxy(thiophosphonooxy)phosphoryl]oxy}phosphoryl]-alpha-L-arabinofuranosyl}-3,9-dihydro-1H-purine-2,6-dione, MAGNESIUM ION, ... (11 entities in total)
• Functional Keywords: small gtpase, mtorc1 activation, amino acid signaling, lysosome, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 173278.65

Authors

Fromm, S.A.,Hurley, J.H. (deposition date: 2020-04-11, release date: 2020-09-02, Last modification date: 2024-03-06)

Primary citation

Fromm, S.A.,Lawrence, R.E.,Hurley, J.H.
Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9.
Nat.Struct.Mol.Biol., 27:1017-1023, 2020

PubMed 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.

PubMed: 32868926
DOI: 10.1038/s41594-020-0490-9

Experimental method

ELECTRON MICROSCOPY (3.2 Å)