Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms
Name
9545.full.pdf
Description
Published version
Size
1.32 MB
Format
Adobe PDF
Checksum (MD5)
9a4baf5f38e87dd390adeb6be161879d
Author(s)
Shen, Kuang
Sabatini, David M
Date Issued
2018
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Version
Final published version
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses a unique "locking" mechanism to stabilize its active (GTPRagA-RagCGDP) or inactive (GDPRagA-RagCGTP) nucleotide states. The Ragulator complex tethers the Rag heterodimer to the lysosomal surface, and the SLC38A9 transmembrane protein is a lysosomal arginine sensor that upon activation stimulates mTORC1 activity through the Rag GTPases. How Ragulator and SLC38A9 control the nucleotide loading state of the Rag GTPases remains incompletely understood. Here we find that Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state. Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP-to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Altogether, Ragulator and SLC38A9 act on the Rag GTPases to activate themTORC1 pathway in response to nutrient sufficiency.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1073/PNAS.1811727115
