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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)
Related entries: 6s6a, 6s6d, 6sb0

Cited: 54 times
EuropePMC logo PMID: 31601764

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)

  1. The mTOR-Autophagy Axis and the Control of Metabolism. Deleyto-Seldas N, Efeyan A. Front Cell Dev Biol 9 655731 (2021)
  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)

Articles citing this publication (37)

  1. A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. Napolitano G, Di Malta C, Esposito A, de Araujo MEG, Pece S, Bertalot G, Matarese M, Benedetti V, Zampelli A, Stasyk T, Siciliano D, Venuta A, Cesana M, Vilardo C, Nusco E, Monfregola J, Calcagnì A, Di Fiore PP, Huber LA, Ballabio A. Nature 585 597-602 (2020)
  2. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Lawrence RE, Fromm SA, Fu Y, Yokom AL, Kim DJ, Thelen AM, Young LN, Lim CY, Samelson AJ, Hurley JH, Zoncu R. Science 366 971-977 (2019)
  3. Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM. Cell 179 1319-1329.e8 (2019)
  4. NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C. Davis OB, Shin HR, Lim CY, Wu EY, Kukurugya M, Maher CF, Perera RM, Ordonez MP, Zoncu R. Dev Cell 56 260-276.e7 (2021)
  5. Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex. Cui Z, Napolitano G, de Araujo MEG, Esposito A, Monfregola J, Huber LA, Ballabio A, Hurley JH. Nature 614 572-579 (2023)
  6. Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9. Fromm SA, Lawrence RE, Hurley JH. Nat Struct Mol Biol 27 1017-1023 (2020)
  7. Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1. Shin HR, Citron YR, Wang L, Tribouillard L, Goul CS, Stipp R, Sugasawa Y, Jain A, Samson N, Lim CY, Davis OB, Castaneda-Carpio D, Qian M, Nomura DK, Perera RM, Park E, Covey DF, Laplante M, Evers AS, Zoncu R. Science 377 1290-1298 (2022)
  8. Structure of the nutrient-sensing hub GATOR2. Valenstein ML, Rogala KB, Lalgudi PV, Brignole EJ, Gu X, Saxton RA, Chantranupong L, Kolibius J, Quast JP, Sabatini DM. Nature 607 610-616 (2022)
  9. A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids. Gollwitzer P, Grützmacher N, Wilhelm S, Kümmel D, Demetriades C. Nat Cell Biol 24 1394-1406 (2022)
  10. Location-specific inhibition of Akt reveals regulation of mTORC1 activity in the nucleus. Zhou X, Zhong Y, Molinar-Inglis O, Kunkel MT, Chen M, Sun T, Zhang J, Shyy JY, Trejo J, Newton AC, Zhang J. Nat Commun 11 6088 (2020)
  11. Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation. Caligaris M, Nicastro R, Hu Z, Tripodi F, Hummel JE, Pillet B, Deprez MA, Winderickx J, Rospert S, Coccetti P, Dengjel J, De Virgilio C. Elife 12 e84319 (2023)
  12. Cryo-EM structures of the human GATOR1-Rag-Ragulator complex reveal a spatial-constraint regulated GAP mechanism. Egri SB, Ouch C, Chou HT, Yu Z, Song K, Xu C, Shen K. Mol Cell 82 1836-1849.e5 (2022)
  13. Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation. Jansen RM, Peruzzo R, Fromm SA, Yokom AL, Zoncu R, Hurley JH. Sci Adv 8 eadd2926 (2022)
  14. Regulation of human mTOR complexes by DEPTOR. Wälchli M, Berneiser K, Mangia F, Imseng S, Craigie LM, Stuttfeld E, Hall MN, Maier T. Elife 10 e70871 (2021)
  15. Research Support, N.I.H., Intramural Drugging multiple same-allele driver mutations in cancer. Nussinov R, Zhang M, Maloney R, Jang H. Expert Opin Drug Discov 16 823-828 (2021)
  16. Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization. Berquez M, Chen Z, Festa BP, Krohn P, Keller SA, Parolo S, Korzinkin M, Gaponova A, Laczko E, Domenici E, Devuyst O, Luciani A. Nat Commun 14 3994 (2023)
  17. A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Gong GQ, Bilanges B, Allsop B, Masson GR, Roberton V, Askwith T, Oxenford S, Madsen RR, Conduit SE, Bellini D, Fitzek M, Collier M, Najam O, He Z, Wahab B, McLaughlin SH, Chan AWE, Feierberg I, Madin A, Morelli D, Bhamra A, Vinciauskaite V, Anderson KE, Surinova S, Pinotsis N, Lopez-Guadamillas E, Wilcox M, Hooper A, Patel C, Whitehead MA, Bunney TD, Stephens LR, Hawkins PT, Katan M, Yellon DM, Davidson SM, Smith DM, Phillips JB, Angell R, Williams RL, Vanhaesebroeck B. Nature 618 159-168 (2023)
  18. Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition. Figlia G, Müller S, Hagenston AM, Kleber S, Roiuk M, Quast JP, Ten Bosch N, Carvajal Ibañez D, Mauceri D, Martin-Villalba A, Teleman AA. Nat Cell Biol 24 1407-1421 (2022)
  19. TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy. Kim M, Lu L, Dvornikov AV, Ma X, Ding Y, Zhu P, Olson TM, Lin X, Xu X. Int J Mol Sci 22 5494 (2021)
  20. Molecular mechanism of S-adenosylmethionine sensing by SAMTOR in mTORC1 signaling. Tang X, Zhang Y, Wang G, Zhang C, Wang F, Shi J, Zhang T, Ding J. Sci Adv 8 eabn3868 (2022)
  21. EGOC inhibits TOROID polymerization by structurally activating TORC1. Prouteau M, Bourgoint C, Felix J, Bonadei L, Sadian Y, Gabus C, Savvides SN, Gutsche I, Desfosses A, Loewith R. Nat Struct Mol Biol 30 273-285 (2023)
  22. A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity. Khamsing D, Lebrun S, Fanget I, Larochette N, Tourain C, de Sars V, Brunstein M, Oheim M, Carrel D, Darchen F, Desnos C. Mol Brain 14 112 (2021)
  23. An interdomain hydrogen bond in the Rag GTPases maintains stable mTORC1 signaling in sensing amino acids. Egri SB, Shen K. J Biol Chem 297 100861 (2021)
  24. Evaluation of the Binding Kinetics of RHEB with mTORC1 by In-Cell and In Vitro Assays. Shams R, Ito Y, Miyatake H. Int J Mol Sci 22 8766 (2021)
  25. Role of FLCN Phosphorylation in Insulin-Mediated mTORC1 Activation and Tumorigenesis. Wang G, Chen L, Lei X, Qin S, Geng H, Zheng Y, Xia C, Yao J, Meng T, Deng L. Adv Sci (Weinh) 10 e2206826 (2023)
  26. Structural Insights into the Activation of mTORC1 on the Lysosomal Surface. Park JH, Lee G, Blenis J. Trends Biochem Sci 45 367-369 (2020)
  27. Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace. Heimhalt M, Berndt A, Wagstaff J, Anandapadamanaban M, Perisic O, Maslen S, McLaughlin S, Yu CW, Masson GR, Boland A, Ni X, Yamashita K, Murshudov GN, Skehel M, Freund SM, Williams RL. Elife 10 e68799 (2021)
  28. Development of an RHEB-Targeting Peptide To Inhibit mTORC1 Kinase Activity. Shams R, Ito Y, Miyatake H. ACS Omega 7 23479-23486 (2022)
  29. Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells. Doxsey DD, Tettoni SD, Egri SB, Shen K. J Biol Chem 299 104880 (2023)
  30. The FUSION protein crystallization screen. Gorrec F, Bellini D. J Appl Crystallogr 55 310-319 (2022)
  31. News A transient protein megacomplex that controls degradation of cell components. Nature (2023)
  32. Genetic Targeting of dSAMTOR, A Negative dTORC1 Regulator, during Drosophila Aging: A Tissue-Specific Pathology. Katarachia SA, Markaki SP, Velentzas AD, Stravopodis DJ. Int J Mol Sci 24 9676 (2023)
  33. Glomerular mTORC1 activation was associated with podocytes to endothelial cells communication in lupus nephritis. Liu X, Mao Z, Yuan M, Li L, Tan Y, Qu Z, Chen M, Yu F. Lupus Sci Med 10 e000896 (2023)
  34. Mechanism of GTPase activation of a prokaryotic small Ras-like GTPase MglA by an asymmetrically interacting MglB dimer. Chakraborty S, Kanade M, Gayathri P. J Biol Chem 300 107197 (2024)
  35. New insights into GATOR2-dependent interactions and its conformational changes in amino acid sensing. Yang C, Sun X, Wu G. Biosci Rep 44 BSR20240038 (2024)
  36. Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma. Liu Y, Zhu Y, Chen H, Zhou J, Niu P, Shi D. BMC Complement Med Ther 23 336 (2023)
  37. Structure of the Schizosaccharomyces pombe Gtr-Lam complex reveals evolutionary divergence of mTORC1-dependent amino acid sensing. Tettoni SD, Egri SB, Doxsey DD, Veinotte K, Ouch C, Chang JY, Song K, Xu C, Shen K. Structure 31 1065-1076.e5 (2023)


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