# A Molecular Study of Rag GTPase-Dependent Amino Acid Sensing

> **NIH NIH K22** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $204,163

## Abstract

Project Summary / Abstract
 The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a key regulator of cell growth and
proliferation. Upon activation in a favorable, nutrient-rich environment, mTORC1 triggers anabolic reactions
and inhibits catabolism. Nutrient signals, especially amino acid signals, are transmitted to mTORC1 through a
series of protein complexes, which ultimately converge on the Rag GTPases, a heterodimeric GTPase that
directly recruits mTORC1 to the lysosomal surface. Recent discovery of the Rag GTPases and their regulators
has revealed a key intermediate between amino acid sufficiency and mTORC1 activation. However, the
molecular mechanisms of how these protein machineries collaborate to transmit the amino acid signal are still
elusive. Understanding the mechanistic details of this pathway will require: (1) determination of the structures
of key protein components to reveal domains and residues that are critical for their biological functions, and (2)
biochemical analyses to define protein functions at the mechanistic level and quantify the effect of specific
perturbations. In this proposal, we aim to develop biochemical and biophysical tools to study Rag-dependent
amino acid sensing at the molecular level. Specifically, we aim to use structural biology tools to directly
visualize the protein complexes that mediate this process (Aim 1), and enzymatic kinetics assays to quantify
the functions of the Rag GTPases and their regulators (Aim 2). Further, we plan to reconstitute an in vitro
system to recapitulate Rag-dependent amino acid sensing (Aim 3), and directly visualize the organization of
these protein machines at the single-molecule level (Aim 4). The approaches developed here will provide a
unified model and yield novel insights into this important biological process.

## Key facts

- **NIH application ID:** 10070595
- **Project number:** 5K22CA241362-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Kuang Shen
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $204,163
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070595

## Citation

> US National Institutes of Health, RePORTER application 10070595, A Molecular Study of Rag GTPase-Dependent Amino Acid Sensing (5K22CA241362-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10070595. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*