Oliver's mTOR Atlas Evidence Platform
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Pathway link LEU-SESN2

Leucine Sestrin2

Leucine inhibits Sestrin2.

Leucine sticks to a pocket inside Sestrin2 and makes it let go of the next protein in line – that's how the cell notices leucine is around.

Leucine binds a pocket inside Sestrin2 with roughly 20 uM affinity - close to the concentration at which cells actually feel leucine coming and going. The bound sensor can no longer hold GATOR2, so leucine effectively switches the brake off.

The conditions it holds under

Affinity was measured in vitro; whether the same 20 uM setpoint holds in tissues with different leucine transport is untested. SHIM2026 is a 2026 rat study (dexamethasone-induced muscle atrophy, not an ageing model) with human myotubes; it tests a leucine-mimetic prodrug and supports Sestrin2-dependent mTORC1 activation, not the 20 uM leucine setpoint.

Time it takes
seconds
Step
direct (one molecule acts on the other)
Measured in
human cells, rat
Where in the cell
cytosol
Reaches people?
plausible in people, not shown directly
How settled
settled in the literature

Studies behind it

YearEvidenceStudy
2015 M Sestrin2 is a leucine sensor for the mTORC1 pathwayWOL2015 Sestrin2 is a direct leucine sensor whose leucine binding releases GATOR2 to activate mTORC1.
2015 M Structural basis for leucine sensing by the Sestrin2-mTORC1 pathwaySAX2015 Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor.
2026 A D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.SHIM2026 DLMEH, a D-leucine ester prodrug, binds Sestrin2 with leucine-like potency (Kd 28.3 uM, equivalent to L-leucine) and activates mTORC1 in a Sestrin2-dependent way. It restored protein synthesis in human myotubes and preserved muscle mass, grip strength and endurance in a rat dexamethasone-induced atrophy model (not an ageing sarcopenia model).

Points the other way

No study in the Atlas contradicts this link. That means none in this curated set, not none in the literature.

Who has checked this

Checked by
No researcher outside the project has checked this link yet.
Curator sign-off
Not signed off yet. This link was drafted with AI help and has not been reviewed link by link; treat it as a proposal until it is.
Curated by
Oliver Barton, with AI help for drafting; see how links are checked.

“Inhibits” describes the effect on the target's activity, not on how much of it there is.

“How settled” describes how far researchers in the field agree. It is not the same as the sign-off above, which only says whether a named curator has checked this page.

If this link rests on your own work: a click on “This looks right” below, or a short note through “Report an error”, helps us more than anything else on this page.

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