title: Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway.
abstract: Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Saxton
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Knockenhauer
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Wolfson
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Chantranupong
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pacold
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Schwartz
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D007930:Leucine / Q000737:chemistry* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D053858:Metabolic Networks and Pathways; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D007930:Leucine; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D058570:TOR Serine-Threonine Kinases; C465398:SESN2 protein, human; D000084622:Sestrins