Sunday, November 24, 2024 11/24/2024

Deciphering the Mechanisms of Pathogenic Ferrous Iron Acquisition and Eukaryotic Post-Translational Arginylation

Award Number: R35GM133497
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary This research program focuses on two inadequately understood metalloprotein systems that are linked to health and human disease and aims to uncover the mechanistic underpinnings of these essential biological processes. The first biological process of focus is bacterial ferrous iron (Fe2+) generation, acquisition, and sensing. The chief prokaryotic Fe2+ acquisition system is the Feo system, which is present in nearly all bacteria and is used by pathogens to establish infection in mammalian hosts. Our previous work has begun to unravel the mechanistic details of this important iron acquisition pathway. Importantly, there is an emerging connection between Feo and additional membrane-bound proteins that function more broadly in bacterial Fe2+ homeostasis through the sensing Fe2+ to control biofilm formation (BqsR/S) and the utilization of Fe3+-siderophores to supply Fe2+ to the Feo system (membrane ferric reductases or mFRs). This proposal outlines a comprehensive approach to study these three systems (Feo, Bqs, mFRs) both in vitro and in vivo. Leveraging structural, spectroscopic, and biochemical analyses, this proposal aims to define the mechanism of bacterial Fe2+ generation, acquisition, and sensing, which will position future researchers to explore the urgent but broadly impactful possibility that these systems may be exploited to combat bacterial virulence. The second biological process of focus is eukaryotic post-translational arginylation, catalyzed by the enzyme arginyltransferase 1 (ATE1). ATE1-catalyzed arginylation typically targets the N-terminus of proteins, altering protein function and fate in vivo. Normal ATE1 activity is critical for neurogenesis, cardiovascular development, cancer, and viral infections, but the structural and mechanistic details of ATE1-mediated arginylation are sorely lacking, prohibiting the targeting of this system for therapeutic intervention. Our previous work has uncovered the structure of yeast ATE1 for the first time, has shown that ATE1s are O2-sensitive [Fe-S] proteins, and has developed a mechanistic framework for post-translational arginylation. This proposal aims to uncover the structure of the arginylation complex and its link to O2 sensitivity, to determine the structure of a mammalian ATE1, and to understand the evolution of ATE1. To achieve this goal, this proposal combines in vitro and in vivo structural, biochemical, and functional methods to elucidate the components of post-translation arginylation in order to design small molecules that target ATE1 for intervention. Combined, the results from this proposal hold the promise to aid in the development of therapeutics to abrogate bacterial virulence linked to iron homeostasis and to treat cellular diseases linked to post-translational arginylation.


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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	6	11/6/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $280,589 )
2024	2024	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	6	6/25/2024	COMPETING CONTINUATION	$280,589
														Subtotal = $280,589

Issue Date FY: 2023 ( Subtotal = $299,136 )
2023	2023	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	001	5	6/30/2023	SUPPLEMENT FOR EXPANSION	$11,784
2023	2023	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	5	6/29/2023	NON-COMPETING CONTINUATION	$287,352
														Subtotal = $299,136

Issue Date FY: 2022 ( Subtotal = $557,598 )
2022	2022	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	001	4	6/9/2022	NON-COMPETING CONTINUATION	$287,352
2022	2022	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	3	5/26/2022	SUPPLEMENT FOR EXPANSION	$199,540
2022	2022	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	002	4	6/10/2022	SUPPLEMENT FOR EXPANSION	$70,706
														Subtotal = $557,598

Issue Date FY: 2021 ( Subtotal = $346,274 )
2021	2021	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	001	3	8/20/2021	SUPPLEMENT FOR EXPANSION	$58,922
2021	2021	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	3	5/28/2021	NON-COMPETING CONTINUATION	$287,352
														Subtotal = $346,274

Issue Date FY: 2020 ( Subtotal = $264,032 )
2020	2020	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	2	6/1/2020	NON-COMPETING CONTINUATION	$264,032
														Subtotal = $264,032

Issue Date FY: 2019 ( Subtotal = $264,880 )
2019	2019	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	1	8/2/2019	NEW	$264,880
														Subtotal = $264,880

Grand Total All Awards = $2,012,509

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Deciphering the Mechanisms of Pathogenic Ferrous Iron Acquisition and Eukaryotic Post-Translational Arginylation

Award Number: R35GM133497

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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