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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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Project Summary This MIRA proposal aims to solve critical gaps in knowledge of two poorly understood protein systems that are linked to health and human disease. To accomplish this proposal, the designed studies combine structural, inorganic, and biochemical approaches with an innovative metallocentric point of view that is essential yet has remained chiefly unexplored for these proteins. The first proposed system of study is the ferrous (Fe2+) iron uptake (Feo) system, which is present in nearly all bacteria and is used by pathogens to establish infection in mammalian hosts. Previous studies on Feo have either been too large or too small in scope, leading to a fragmented and inconclusive understanding with little insight into mechanism. This proposal outlines a comprehensive approach to study the Feo system at the protein level. Leveraging structural, spectroscopic, and biochemical analyses, this proposal aims to delineate the mechanism of prokaryotic Fe2+ transport, which will position future researchers to explore the urgent but broadly impactful possibility that Feo may be exploited to combat bacterial virulence. The second proposed system of study focuses on the arginine transferases (known as ATE1s), which are enzymes that arginylate the N-terminus of peptides or proteins, subsequently triggering their degradation via the ubiquitin-proteasome system. Normal ATE1 function is critical for neurogenesis and cardiovascular development, but structural and mechanistic details of ATE1-mediated arginylation are sorely lacking, prohibiting the targeting of this system for therapeutic intervention. Exciting results indicate ATE1s may be iron-containing enzymes, but the function of iron in this system remains unknown. This proposal aims to delineate the structure and mechanism of ATE1s, including the potential regulatory role of iron in these enzymes. To achieve this goal, this proposal combines protein- level structural, biochemical, and spectroscopic methods to elucidate the arginylation mechanism of ATE1s, and to resolve how iron controls this process. Once determined, this molecular-level detail will be invaluable 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 and to treat neurological and cardiovascular diseases.


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 = $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 = $1,731,920

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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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