8DHB

Active FLCN GAP complex

Summary for 8DHB

• Entry DOI: 10.2210/pdb8dhb/pdb
• EMDB information: 27435
• Descriptor: Ras-related GTP-binding protein C, Folliculin, [(2~{R},3~{S},4~{R},5~{R})-5-[2,6-bis(oxidanylidene)-3~{H}-purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl phosphono hydrogen phosphate, ... (13 entities in total)
• Functional Keywords: flcn, rag-ragulator, gtpase activating protein, mtorc1 signaling, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 419249.26

Authors

Jansen, R.M.,Hurley, J.H. (deposition date: 2022-06-25, release date: 2022-09-28, Last modification date: 2024-10-09)

Primary citation

Jansen, R.M.,Peruzzo, R.,Fromm, S.A.,Yokom, A.L.,Zoncu, R.,Hurley, J.H.
Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation.
Sci Adv, 8:eadd2926-eadd2926, 2022

PubMed Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) is a RagC/D guanosine triphosphatase (GTPase)-activating protein (GAP) that regulates mTORC1 phosphorylation of MiT-TFE transcription factors, controlling lysosome biogenesis and autophagy. We determined the cryo-electron microscopy structure of the active FLCN complex (AFC) containing FLCN, FNIP2, the N-terminal tail of SLC38A9, the RagA:RagC GTPase dimer, and the Ragulator scaffold. Relative to the inactive lysosomal FLCN complex structure, FLCN reorients by 90°, breaks contact with RagA, and makes previously unseen contacts with RagC that position its Arg finger for catalysis. Disruption of the AFC-specific interfaces of FLCN and FNIP2 with RagC eliminated GAP activity and led to nuclear retention of TFE3, with no effect on mTORC1 substrates S6K or 4E-BP1. The structure provides a basis for regulation of an mTORC1 substrate-specific pathway and a roadmap to discover MiT-TFE family selective mTORC1 antagonists.

PubMed: 36103527
DOI: 10.1126/sciadv.add2926

Experimental method

ELECTRON MICROSCOPY (3.53 Å)