PRAS40
Insulin-regulated inhibitor subunit of mTORC1. Insulin triggers Akt to phosphorylate PRAS40, which lifts one inhibitory subunit off the complex; that on its own is not the on-switch, as most of the insulin input runs through the TSC2/Rheb arm.
A plug in mTORC1's substrate slot. A brake on mTORC1 that insulin can release. When insulin signals arrive, a kinase called Akt tags this protein and it lets go of mTORC1. That alone does not switch mTORC1 on, though: most of the insulin signal travels through the TSC2/Rheb route.
AKT1S1. Competes with substrate for the Raptor TOS-motif site; its displacement is a substrate-access mechanism, not a change in kinase catalytic rate.
TL;DR. PRAS40 appears in 4 curated studies in Oliver's mTOR Atlas: 4 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| PRAS40 inhibits mTORC1 mechanism: competitive-inhibition · this link in full · on the map table | Untagged PRAS40 sits inside mTORC1 and blocks it, like a built-in plug. Unphosphorylated PRAS40 sits in the substrate groove of mTORC1 and blocks it - a built-in plug. Unphosphorylated PRAS40 sits in the substrate groove of mTORC1 and blocks it - a built-in plug. Holds under: Human cell biochemistry and a cryo-EM structure (SAN2007, YAN2017). Shows the plug mechanism in cells and in structure; its effect in whole animals and in people is not tested here. plausible in people, not shown directly · settled in the literature | M | SAN2007, YAN2017 |
| Akt/PKB inhibits PRAS40 mechanism: phosphorylation · this link in full · on the map table | Akt tags PRAS40, which then gets pulled away from mTORC1 – a second way insulin releases a brake. Akt phosphorylates PRAS40, which then gets sequestered away from mTORC1 - a second, parallel way insulin lifts a brake. Akt phosphorylates PRAS40, which then gets sequestered away from mTORC1 - a second, parallel way insulin lifts a brake. Holds under: Three 2007 studies in cultured mammalian cells. Not tested in whole animals or in people, and how much this branch adds beside Akt's route through TSC2 is not measured. plausible in people, not shown directly · settled in the literature | M | SAN2007, VAN2007, OSH2007 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 4 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2017 | M | Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40 YAN2017 Structures reveal how RHEB allosterically activates and PRAS40 inhibits mTORC1. |
| 2007 | M | PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase SAN2007 Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity. |
| 2007 | M | The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1 OSH2007 PRAS40 is a physiological raptor-bound substrate and inhibitor of mTORC1. |
| 2007 | M | Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 VAN2007 Insulin signals to mTORC1 through Akt phosphorylation of the inhibitor PRAS40. |
Related entities
Thank you. Your answer was counted anonymously.