Conformational changes in Rag GTPases orchestrate signaling activities of mTORC1
EMSL Project ID
51139
Abstract
The mTORC1 protein kinase is a growth regulator that responds to stimuli, including nutrients and growth factors. Amino acids promote its translocation to the lysosomal surface, where it interacts with the Rag GTPase-Ragulator complex. The Rag GTPases are heterodimeric, and their nucleotide binding states change in response to nutrients, thus regulating the activities of the mTORC1 pathway.Our main goal is to understand how the mechanism of Rag nucleotide switching works on a structural level.
To this end, we will use cryo-EM to determine structures of the Rag-Ragulator complex in four possible nucleotide binding states (GTP-GTP, GTP-GDP, GDP-GTP and GDP-GDP). This research will open doors to investigation of the switching mechanism in cells and in vitro through mutagenesis. It will also facilitate the development of small chemical probes that can imitate nutrient signals, and therefore precisely modulate the mTORC1 pathway in cells, and potentially also in patients with deregulated mTORC1 signaling.
Project Details
Start Date
2019-11-10
End Date
2020-09-10
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members