The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation
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 GDP :RagC GDP.BeFx- 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 164 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.
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“The regulation of RagC and RagD is somewhat less well understood, but the FLCN complex has been shown to act as a GAP for these GTPases 174–177.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [177]
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Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M. (2010) · Cell · doi:10.1016/j.cell.2010.02.024 · Cited by 2,464 · cited 2×
“The Rag-Ragulator complex consists of two Rag GTPases (commonly referred to as Rags) that function as obligate heterodimers and are anchored to the lysosomal membrane by the pentameric scaffold Ragulator ( 13 , 14 ).”
Self-citationBar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080 · cited 1×
“Conversion between active and inactive states is regulated by the RagA/B-specific GAP, GAP activity towards Rags 1 (GATOR1), and by the RagC/D-specific GAP, FLCN:FLCN-interacting protein 2 (FNIP2) ( 16 , 17 ).”
The lysosome as a cellular centre for signalling, metabolism and quality control
Lawrence, R. E., & Zoncu, R. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0244-7 · Cited by 920
Self-citationSLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
Rebsamen, M., Pochini, L., Stasyk, T., de Araújo, M. E. G., Galluccio, M., Kandasamy, R. K., Snijder, B., Fauster, A., Rudashevskaya, E. L., Bruckner, M., et al. (2015) · Nature · doi:10.1038/nature14107 · Cited by 673
Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPases
Petit, C. S., Roczniak-Ferguson, A., & Ferguson, S. M. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201307084 · Cited by 355
Jeong, J.-H., Lee, K.-H., Kim, Y.-M., Kim, D.-H., Oh, B.-H., & Kim, Y.-G. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.c112.384420 · Cited by 68 · cited 1×
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Cited by
Sorted by citations
Targeting the biology of aging with mTOR inhibitors
Mannick, J. B., & Lamming, D. W. (2023) · Nature Aging · doi:10.1038/s43587-023-00416-y · Cited by 372
Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome
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Metadata
- Authors
- Jansen, R. M., Peruzzo, R., Fromm, S. A., Yokom, A. L., Zoncu, R., & Hurley, J. H.
- Affiliations
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
- Venue
- Science Advances
- Published
- 2022-09-16
- Volume
- 8
- Issue
- 37
- ISSN
- 2375-2548
- PMC
- PMC9473554
- Cited by
- 42
- References
- 6
- Language
- en
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