6sb2 Citations

Architecture of human Rag GTPase heterodimers and their complex with mTORC1.

Abstract

The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.

Articles - 6sb2 mentioned but not cited (1)

  1. Architecture of human Rag GTPase heterodimers and their complex with mTORC1. Anandapadamanaban M, Masson GR, Perisic O, Berndt A, Kaufman J, Johnson CM, Santhanam B, Rogala KB, Sabatini DM, Williams RL. Science 366 203-210 (2019)


Reviews citing this publication (16)

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  2. Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems. James EI, Murphree TA, Vorauer C, Engen JR, Guttman M. Chem Rev 122 7562-7623 (2022)
  3. The Lysosome at the Intersection of Cellular Growth and Destruction. Shin HR, Zoncu R. Dev Cell 54 226-238 (2020)
  4. Regulation of mTORC1 by Upstream Stimuli. Melick CH, Jewell JL. Genes (Basel) 11 E989 (2020)
  5. Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways. Ramirez Reyes JMJ, Cuesta R, Pause A. Front Cell Dev Biol 9 667311 (2021)
  6. Targeting the biology of aging with mTOR inhibitors. Mannick JB, Lamming DW. Nat Aging 3 642-660 (2023)
  7. Structural Insights into TOR Signaling. Tafur L, Kefauver J, Loewith R. Genes (Basel) 11 E885 (2020)
  8. Conserved and Divergent Mechanisms That Control TORC1 in Yeasts and Mammals. Morozumi Y, Shiozaki K. Genes (Basel) 12 88 (2021)
  9. The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging. Fernandes SA, Demetriades C. Front Aging 2 707372 (2021)
  10. Regulation of mTORC1 by amino acids in mammalian cells: A general picture of recent advances. Zhang S, Lin X, Hou Q, Hu Z, Wang Y, Wang Z. Anim Nutr 7 1009-1023 (2021)
  11. Coordination of Rheb lysosomal membrane interactions with mTORC1 activation. Angarola B, Ferguson SM. F1000Res 9 F1000 Faculty Rev-450 (2020)
  12. Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin. de Martín Garrido N, Aylett CHS. Front Cell Dev Biol 8 108 (2020)
  13. Mechanism of Activation of Mechanistic Target of Rapamycin Complex 1 by Methionine. Kitada M, Xu J, Ogura Y, Monno I, Koya D. Front Cell Dev Biol 8 715 (2020)
  14. Activation Mechanisms of the VPS34 Complexes. Ohashi Y. Cells 10 3124 (2021)
  15. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease. Goul C, Peruzzo R, Zoncu R. Nat Rev Mol Cell Biol 24 857-875 (2023)
  16. Getting Lost in the Cell-Lysosomal Entrapment of Chemotherapeutics. Zhai X, El Hiani Y. Cancers (Basel) 12 E3669 (2020)

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