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dc.contributor.authorKnockenhauer, Kevin E.
dc.contributor.authorSchwartz, Thomas U.
dc.contributor.authorSaxton, Robert Andrew
dc.contributor.authorChantranupong, Lynne
dc.contributor.authorSabatini, David
dc.date.accessioned2018-07-03T19:22:01Z
dc.date.available2018-07-03T19:22:01Z
dc.date.issued2016-08
dc.date.submitted2016-02
dc.identifier.issn0028-0836
dc.identifier.issn1476-4687
dc.identifier.urihttp://hdl.handle.net/1721.1/116774
dc.description.abstractThe mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7).Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant R01CA103866)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant AI47389)en_US
dc.description.sponsorshipUnited States. Department of Defense (Award W81XWH-07-0448)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant F31 CA180271)en_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/NATURE19079en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePMCen_US
dc.titleMechanism of arginine sensing by CASTOR1 upstream of mTORC1en_US
dc.typeArticleen_US
dc.identifier.citationSaxton, Robert A. et al. “Mechanism of Arginine Sensing by CASTOR1 Upstream of mTORC1.” Nature 536, 7615 (August 2016): 229–233 © 2016 Macmillan Publishers Limited, part of Springer Natureen_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorSaxton, Robert Andrew
dc.contributor.mitauthorChantranupong, Lynne
dc.contributor.mitauthorSabatini, David
dc.relation.journalNatureen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-07-03T18:18:05Z
dspace.orderedauthorsSaxton, Robert A.; Chantranupong, Lynne; Knockenhauer, Kevin E.; Schwartz, Thomas U.; Sabatini, David M.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-9376-3984
dc.identifier.orcidhttps://orcid.org/0000-0001-9388-1633
dc.identifier.orcidhttps://orcid.org/0000-0002-1446-7256
mit.licensePUBLISHER_POLICYen_US


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