SAMTOR is an -adenosylmethionine Sensor for the MTORC1 Pathway

Overview

Journal Science

Specialty Science

Date 2017 Nov 11

PMID 29123071

Citations 271

Authors

Xin Gu

Jose M Orozco

Robert A Saxton

Kendall J Condon

Grace Y Liu

Patrycja A Krawczyk

Sonia M Scaria

J Wade Harper

Steven P Gygi

David M Sabatini

Affiliations

Soon will be listed here.

Abstract

mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor -adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.

Citing Articles

Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.

Xie Z, Lin M, Xing B, Wang H, Zhang H, Cai Z Sci Adv. 2025; 11(10):eads4957.

PMID: 40053596 PMC: 11887811. DOI: 10.1126/sciadv.ads4957.

Pectin-Zein-IPA nanoparticles promote functional recovery and alleviate neuroinflammation after spinal cord injury.

Chen X, Wang B, Al Mamun A, Du K, Wang S, Hu Q J Nanobiotechnology. 2025; 23(1):152.

PMID: 40016738 PMC: 11869623. DOI: 10.1186/s12951-025-03224-1.

Determination of Nutrient Ligand-Sensor Binding Affinity.

Gu X Methods Mol Biol. 2025; 2882:163-178.

PMID: 39992509 DOI: 10.1007/978-1-0716-4284-9_8.

Serum metabolomics analysis reveals a novel association between maternal metabolism and fetal survival in sows fed diets containing differing methionine levels and sources.

Zhou R, Zhe L, Mercier Y, Hu L, Li R, Chen H Anim Nutr. 2025; 20:145-157.

PMID: 39967700 PMC: 11833788. DOI: 10.1016/j.aninu.2024.07.008.

Non-dikarya fungi share the TORC1 pathway with animals, not with Saccharomyces cerevisiae.

Barua D, Plecha M, Muszewska A Sci Rep. 2025; 15(1):5926.

PMID: 39966606 PMC: 11836306. DOI: 10.1038/s41598-025-89635-4.

References

Wyant G, Abu-Remaileh M, Wolfson R, Chen W, Freinkman E, Danai L . mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. Cell. 2017; 171(3):642-654.e12. PMC: 5704964. DOI: 10.1016/j.cell.2017.09.046. View

Gossen M, Bujard H . Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992; 89(12):5547-51. PMC: 49329. DOI: 10.1073/pnas.89.12.5547. View

Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim Y, Akopiants K . Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 2014; 9(4):1281-91. PMC: 4303546. DOI: 10.1016/j.celrep.2014.10.019. View

Sharma S, Watzinger P, Kotter P, Entian K . Identification of a novel methyltransferase, Bmt2, responsible for the N-1-methyl-adenosine base modification of 25S rRNA in Saccharomyces cerevisiae. Nucleic Acids Res. 2013; 41(10):5428-43. PMC: 3664796. DOI: 10.1093/nar/gkt195. View

Saxton R, Knockenhauer K, Wolfson R, Chantranupong L, Pacold M, Wang T . Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2015; 351(6268):53-8. PMC: 4698039. DOI: 10.1126/science.aad2087. View

Sutter B, Wu X, Laxman S, Tu B . Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell. 2013; 154(2):403-15. PMC: 3774293. DOI: 10.1016/j.cell.2013.06.041. View

Peng M, Yin N, Li M . SZT2 dictates GATOR control of mTORC1 signalling. Nature. 2017; 543(7645):433-437. PMC: 5570594. DOI: 10.1038/nature21378. View

Kim E, Goraksha-Hicks P, Li L, Neufeld T, Guan K . Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008; 10(8):935-45. PMC: 2711503. DOI: 10.1038/ncb1753. View

Huttlin E, Bruckner R, Paulo J, Cannon J, Ting L, Baltier K . Architecture of the human interactome defines protein communities and disease networks. Nature. 2017; 545(7655):505-509. PMC: 5531611. DOI: 10.1038/nature22366. View

10.

Wang T, Yu H, Hughes N, Liu B, Kendirli A, Klein K . Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras. Cell. 2017; 168(5):890-903.e15. PMC: 5445660. DOI: 10.1016/j.cell.2017.01.013. View

11.

Law J, Jacobsen S . Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010; 11(3):204-20. PMC: 3034103. DOI: 10.1038/nrg2719. View

12.

Rebsamen M, Pochini L, Stasyk T, de Araujo M, Galluccio M, Kandasamy R . SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015; 519(7544):477-81. PMC: 4376665. DOI: 10.1038/nature14107. View

13.

Bar-Peled L, Chantranupong L, Cherniack A, Chen W, Ottina K, Grabiner B . A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013; 340(6136):1100-6. PMC: 3728654. DOI: 10.1126/science.1232044. View

14.

Bar-Peled L, Schweitzer L, Zoncu R, Sabatini D . Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012; 150(6):1196-208. PMC: 3517996. DOI: 10.1016/j.cell.2012.07.032. View

15.

Miller R, Buehner G, Chang Y, Harper J, Sigler R, Smith-Wheelock M . Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell. 2005; 4(3):119-25. PMC: 7159399. DOI: 10.1111/j.1474-9726.2005.00152.x. View

16.

Wolfson R, Chantranupong L, Wyant G, Gu X, Orozco J, Shen K . KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature. 2017; 543(7645):438-442. PMC: 5360989. DOI: 10.1038/nature21423. View

17.

Sancak Y, Bar-Peled L, Zoncu R, Markhard A, Nada S, Sabatini D . Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010; 141(2):290-303. PMC: 3024592. DOI: 10.1016/j.cell.2010.02.024. View

18.

Wolfson R, Chantranupong L, Saxton R, Shen K, Scaria S, Cantor J . Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2015; 351(6268):43-8. PMC: 4698017. DOI: 10.1126/science.aab2674. View

19.

Chantranupong L, Scaria S, Saxton R, Gygi M, Shen K, Wyant G . The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. Cell. 2016; 165(1):153-164. PMC: 4808398. DOI: 10.1016/j.cell.2016.02.035. View

20.

Kozbial P, Mushegian A . Natural history of S-adenosylmethionine-binding proteins. BMC Struct Biol. 2005; 5:19. PMC: 1282579. DOI: 10.1186/1472-6807-5-19. View