Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

• Autores: Robert A. Saxton, Kevin E. Knockenhauer, Rachel L. Wolfson, Lynne Chantranupong, Michael E. Pacold, Tim Wang, Thomas U. Schwartz, David M. Sabatini
• Localización: Science, ISSN 0036-8075, Vol. 351, Nº 6268, 2016, págs. 53-58
• Idioma: inglés
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• Resumen

  • 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.