# Structural basis of the Ragulator-Rag GTPase complex as a platform for mTOR activation on the lysosomal surface

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $372,900

## Abstract

ABSTRACT
Cellular metabolism comprises biochemical pathways that either convert or consume energy and that are
essential to the cell's survival, growth and proliferation. Key metabolic pathways involving carbohydrates,
amino acids, fatty acids, and other major nutrients are essential for energy homeostasis and macromolecular
synthesis in the cell. In mammalian cells, the target of rapamycin complex-1 (mTORC1) is the master regulator
of cellular metabolic processes, and it ultimately controls the cell's growth and proliferation.
mTORC1 is activated by amino acids through its relocalization from the cytosol to the lysosomal surface,
where it is phosphorylated. It is recruited to the lysosomal surface by the RagB-RagC complex, a GTPase
heterodimer that itself docks on the pentameric Ragulator complex. mTORC1's interaction with Rag depends
on its nucleotide-binding state. When RagB is bound to GDP, the GTPase heterodimer does not interact with
mTORC1. Upon AA activation, Ragulator acts as a guanine exchange factor (GEF) to RagB, helping it to
change from the GDP-bound to a GTP-bound state. The GTPase heterodimer that contains RagB.GTP then
binds to mTORC1 to recruit it to the lysosome where is it activated. Therefore, questions on how Ragulator
functions as a platform for Rag docking, how Rag changes from the inactive RagB.GDP-RagC state to the
active RagB.GTP-RagC state, and how Ragulator facilitates the nucleotide change, are central for the
understanding of the molecular mechanism of mTORC1 activation. In this project, we aim to study the
mechanism of mTORC1 recruitment to the lysosome via Ragulator-Rag using a combination of structural and
biochemical approaches. This will yield a better understanding of cell growth as well as pathogenesis of aging,
diabetes, obesity and various types of cancer.

## Key facts

- **NIH application ID:** 9983710
- **Project number:** 5R01GM121994-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** DANENG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,900
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983710

## Citation

> US National Institutes of Health, RePORTER application 9983710, Structural basis of the Ragulator-Rag GTPase complex as a platform for mTOR activation on the lysosomal surface (5R01GM121994-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9983710. Licensed CC0.

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