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A Molecular Study of Rag GTPase-Dependent Amino Acid Sensing

Award Number: K22CA241362
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2022

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$24,553 )
2023	2022	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	3	4/3/2023	NON-COMPETING CONTINUATION	-$24,553
														Subtotal = -$24,553

Issue Date FY: 2022 ( Subtotal = $204,163 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	001	3	7/28/2022	NON-COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	3	12/23/2021	NON-COMPETING CONTINUATION	$204,163
														Subtotal = $204,163

Issue Date FY: 2021 ( Subtotal = $204,163 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	2	11/23/2020	NON-COMPETING CONTINUATION	$204,163
														Subtotal = $204,163

Issue Date FY: 2020 ( Subtotal = $204,163 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	1	12/12/2019	NEW	$204,163
														Subtotal = $204,163

Grand Total All Awards = $587,936

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A Molecular Study of Rag GTPase-Dependent Amino Acid Sensing

Award Number: K22CA241362

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2022

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