Robert A. Saxton
Solved the structures of the leucine and SAM sensors for mTORC1
Graduate student, Sabatini lab, Whitehead Institute/MIT
As a graduate student in David Sabatini's lab, Robert Saxton took on the structural side of a question the lab had just opened: if Sestrin2 and CASTOR1 are the cell's leucine and arginine sensors, what do they actually look like, and how do they grab their amino acid?
Saxton solved the crystal structure of Sestrin2 bound to leucine, showing a single pocket that specifically fits leucine's hydrophobic side chain, and did the equivalent structural work for CASTOR1 and arginine. Together with colleagues in the lab he also helped identify SAMTOR, the sensor for S-adenosylmethionine, rounding out the set of direct amino-acid and metabolite sensors upstream of mTORC1.
The timeline below follows his structural studies gathered in this Atlas.
Milestones in the Atlas
| Year | Evidence | Study |
|---|---|---|
| 2015 | M | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway SAX2015 Solves the crystal structure of Sestrin2 bound to leucine, explaining how a single pocket confers specificity for this one amino acid. |
| 2016 | M | Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 SAX2016 Solves the structural basis for arginine sensing by CASTOR1, the second direct amino-acid sensor upstream of mTORC1. |
| 2016 | M | The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway CHA2016 Identified CASTOR1 as the direct arginine sensor: when arginine binds CASTOR1, it lets go of GATOR2, switching mTORC1 on. Together with Sestrin2 (leucine) this built the picture of mTORC1 as a cell that literally tastes individual amino acids. |
| 2017 | R | mTOR Signaling in Growth, Metabolism, and Disease SAX2017 Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance. |
| 2017 | M | SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway GU2017 Helps identify SAMTOR as the direct sensor for S-adenosylmethionine upstream of mTORC1. |
| 2022 | M | Structure of the nutrient-sensing hub GATOR2 VAL2022 Cryo-EM structure of human GATOR2: a 1.1 MDa, two-fold symmetric cage built on an octagonal scaffold decorated with eight pairs of WD40 beta-propellers, and a map of where Sestrin2 and CASTOR1 dock. It substantially advances the GATOR2 side of the sensor module, though how GATOR2 inhibits GATOR1 is still not fully settled. |