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Science. 2017 Nov 10;358(6364):813-818. doi: 10.1126/science.aao3265.

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.

Gu X1,2,3,4, Orozco JM1,2,3,4, Saxton RA1,2,3,4, Condon KJ1,2,3,4, Liu GY1,2,3,4, Krawczyk PA1,2,3,4, Scaria SM1,2,3,4, Harper JW5, Gygi SP5, Sabatini DM6,2,3,4.

Author information

1
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
2
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
5
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
6
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.

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 S-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.

PMID:
29123071
PMCID:
PMC5747364
[Available on 2018-11-10]
DOI:
10.1126/science.aao3265
[Indexed for MEDLINE]

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