Hybrid structural model of the RagA/C-Ragulator mTORC1 activation complex.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Hybrid structure |
| Journal | Molecular cell |
| Year | 2017 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.molcel.2017.10.016 · PMID 29107538 · Free full text (PMC5722659) |
The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. The crystal structure of the five-subunit human Ragulator at 1.4 A resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1. EM was used to reconstruct the assembly of the full-length RagA:RagCdimer bound to Ragulator at 16 A resolution, revealing that the G-domains of the Rags project away from the Ragulator core. The combined structural model shows how Ragulator functions as a platform for the presentation of active Rags for mTORC1 recruitment, and might suggest an unconventional mechanism for Rag GEF activity.
| Intervention | Structural (crystal/hybrid) |
| Target | Rag GTPases / Ragulator (Lamtor1-5) / mTORC1 |
| Model | Hybrid structure |
| Effect | Structure of the RagA/C-Ragulator activation complex; Lamtor1 wraps the subunits to form the Rag-binding platform |