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Structural and Molecular Basis of Human ATG3 Activation and Regulation for LC3 Lipid Conjugation in Autophagy

Award Number: R01GM127730
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Structural and Molecular Basis of Human ATG3 Activation and Regulation for LC3 Lipid Conjugation in Autophagy - Abstract Numerous medical and scientific studies indicate that autophagy plays a key role in many diseases including neurodegenerative, infective, and cardiac diseases, and cancer. Reducing or promoting autophagic flux during particular stages of these diseases can improve patient outcomes. To understand this complex relationship between these diseases and autophagy, we must first understand what dictates its timing and regulation. Successful completion of autophagy requires a host of proteins, including Atg3. Atg3 catalyzes the conjugation of Atg8 (or LC3 in mammals) to the PE lipids in the autophagic membrane. The reaction product, Atg8-PE, acts as a marker for autophagic cargo and allows the autophagosomal membrane to be constructed. Previous studies have provided some molecular insights into this reaction; however, our understanding of its mechanism has remained remarkably elusive. In addition, Atg3's function hinges on an N-terminal amphipathic helix (NAH). This helix recognizes highly curved membranes and is required for effective Atg8-PE conjugation in vivo. In this study, we plan to examine the structural and molecular basis of human ATG3 (hATG3) activation and regulation by its interaction with the membrane for this conjugation reaction. In Aim 1, we will determine the structures and dynamics of hATG3 and its thioester intermediate hATG3-LC3. Structural models derived from high-resolution NMR will be validated using in vitro conjugation and in vivo function assays. In Aims 2 and 3, we will analyze the structural and molecular basis of ATG3 activation and regulation, and determine the molecular mechanism that drives the selective binding of ATG3's NAH to strongly curved membranes, respectively. Together, these studies will provide a mechanistic insight into hATG3 activation and regulation for the production of LC3-PE conjugate, a key molecule that triggers membrane expansion and recruits cargos for formation of the autophagosome in autophagy. Our results will contribute to a fundamental understanding of the autophagy process, which may lead to the development of new disease treatments and eventually improve the clinical patient outcome.


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: 2024 ( Subtotal = $0 )
2024	2022	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	4	7/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $379,634 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	4	1/3/2022	NON-COMPETING CONTINUATION	$341,670
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	001	4	7/27/2022	NON-COMPETING CONTINUATION	$37,964
														Subtotal = $379,634

Issue Date FY: 2021 ( Subtotal = $554,634 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	002	3	7/30/2021	SUPPLEMENT FOR EXPANSION	$175,000
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	001	3	3/19/2021	NON-COMPETING CONTINUATION	$37,964
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	3	11/25/2020	NON-COMPETING CONTINUATION	$341,670
														Subtotal = $554,634

Issue Date FY: 2020 ( Subtotal = $379,634 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	001	2	3/17/2020	NON-COMPETING CONTINUATION	$37,964
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	2	12/31/2019	NON-COMPETING CONTINUATION	$341,670
														Subtotal = $379,634

Issue Date FY: 2019 ( Subtotal = $379,634 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	1	1/15/2019	NEW	$379,634
														Subtotal = $379,634

Grand Total All Awards = $1,693,536

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Structural and Molecular Basis of Human ATG3 Activation and Regulation for LC3 Lipid Conjugation in Autophagy

Award Number: R01GM127730

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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