Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway.
Level 5 - mechanism / opinion, no new human data
Bench research and X-ray crystallography; no human data.
PubMed 26586190 · doi:10.1126/science.aad2087
What was done
The authors determined the 2.7 angstrom crystal structure of the nutrient sensor Sestrin2 in complex with leucine. Using this structure, they introduced structure-guided mutations in Sestrin2 to evaluate the relationship between leucine-binding affinity and mTORC1 activation in cellular assays.
What was found
The crystal structure resolved Sestrin2 bound to leucine at 2.7 angstroms, identifying a single binding pocket that coordinates leucine's charged functional groups, recognizes its hydrophobic side chain, and employs an enclosing loop as a lid-latch mechanism. A mutation decreasing Sestrin2 affinity for leucine increased the leucine concentration needed to activate mTORC1 in cells. Exact numerical binding constants and activation thresholds were not reported in the abstract.
Why it matters
This work identifies the structural basis for direct leucine sensing by Sestrin2, clarifying how amino acid availability is biochemically transmitted to the mTORC1 growth-regulatory pathway.
Limits
The study is entirely in vitro and cell-culture-based, lacking in vivo physiological endpoints. The abstract provides no quantitative affinity values, effect sizes, or experimental sample sizes.
Cited by
- supports David Sabatini's lab at MIT published a paper in Science crystallizing and identifying the direct leucine sensor for mTORC1.