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Conformational dynamics and allosteric regulation during stress-responsive metallocofactor assembly

Award Number: R01GM112919
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Conformational dynamics and allosteric regulation during stress-responsive metallocofactor assembly - PROJECT SUMMARY Iron-sulfur (Fe-S) cofactor biogenesis is essential for most living organisms. The continuing long-term goal of this renewal proposal is to characterize protein-protein interactions (PPIs) critical for bacterial Fe-S cluster biogenesis by the Suf (sulfur formation) pathway, which is ubiquitous in prokaryotes including important pathogens. Due to the toxic nature of free iron and sulfide in cells, Fe-S cluster assembly and trafficking is highly choreographed by a complex network of protein partners. In Escherichia coli, Suf has evolved to act as an emergency pathway that is activated under conditions of oxidative stress or iron starvation. In other bacteria, such as Mycobacterium tuberculosis and Enterococcus faecalis, the Suf pathway is the sole source for Fe-S clusters, making it an essential pathway and potential target for antibiotic development. The Suf pathway consists of six proteins, SufABCDSE. SufS is a cysteine desulfurase that mobilizes persulfide (So) from L-cysteine. Persulfide generated by SufS must be transferred to the transpersulfurase protein, SufE, prior to delivery to SufB on the SufBC2D cluster scaffold. In vivo, Fe-S cluster assembly on the SufBC2D scaffold is dependent on the ATPase activity of SufC and acquisition of iron, which is likely regulated by SufD. Following cluster assembly, SufBC2D transfers the nascent cluster to SufA for downstream trafficking. While simple functional assignments are available for proteins in the Suf pathway, lack of detailed mechanistic descriptions prevents the rational design of small molecules to effectively disrupt the assembly process. During the previous funding period, regulation of the sulfur mobilization step was characterized in detail. The overall goal of this proposal is to investigate PPIs regulating cluster assembly and downstream trafficking. The hypothesis is that PPIs important for regulating cluster assembly and trafficking are governed by changes in the structure/dynamics of Suf proteins through the assembly process. We will test this hypothesis using a complementary, multi-pronged approach including hydrogen/deuterium exchange mass spectrometry (HDX-MS), protein crystallography, biophysical/biochemical characterization, and genetic complementation assays. To accomplish this broad approach, a research team with diverse backgrounds and a productive track-record has been assembled. The specific aims of this renewal proposal include: (1) characterization of Fe-S cluster-based regulation of sequential protein-protein interactions with SufBC2D, (2) determination of the role of ATP in the function of SufBC2D, and (3) identification of cluster trafficking interactions between the Suf system and the broader pool of Fe-S cluster carrier proteins. Completion of the experiments described in the proposal will provide a rigorous mechanistic description of how Fe-S cluster assembly and trafficking is regulated in the Suf pathway. These results can be leveraged to design potential antibiotics targeting bacterial Fe-S cluster pathways and may inspire novel therapeutic interventions for defects in analogous human pathways.


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 = $300,204 )
2023	2023	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	8	4/7/2023	NON-COMPETING CONTINUATION	$300,204
														Subtotal = $300,204

Issue Date FY: 2022 ( Subtotal = $306,080 )
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	001	7	5/5/2022	SUPPLEMENT FOR EXPANSION	$3,841
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	002	7	6/29/2022	NON-COMPETING CONTINUATION	$29,862
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	7	4/6/2022	NON-COMPETING CONTINUATION	$268,745
2022	2018	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	003	4	9/26/2022	NON-COMPETING CONTINUATION	$3,632
														Subtotal = $306,080

Issue Date FY: 2021 ( Subtotal = $297,086 )
2021	2021	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	6	3/31/2021	NON-COMPETING CONTINUATION	$297,086
2021	2020	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	002	5	4/13/2021	COMPETING CONTINUATION	$3,632
2021	2018	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	001	4	4/13/2021	NON-COMPETING CONTINUATION	-$3,632
														Subtotal = $297,086

Issue Date FY: 2020 ( Subtotal = $297,601 )
2020	2020	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	002	5	3/17/2020	COMPETING CONTINUATION	$297,601
2020	2018	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	001	4	3/9/2020	NON-COMPETING CONTINUATION	$0
2020	2018	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	4	11/11/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $297,601

Issue Date FY: 2018 ( Subtotal = $268,060 )
2018	2018	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	001	4	5/23/2018	NON-COMPETING CONTINUATION	$26,806
2018	2018	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	4	12/20/2017	NON-COMPETING CONTINUATION	$241,254
														Subtotal = $268,060

Issue Date FY: 2017 ( Subtotal = $300,200 )
2017	2017	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	001	3	8/2/2017	NON-COMPETING CONTINUATION	$30,021
2017	2017	UNIVERSITY OF ALABAMA	301 ROSE ADMINISTRATION BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	3	12/23/2016	NON-COMPETING CONTINUATION	$270,179
														Subtotal = $300,200

Issue Date FY: 2016 ( Subtotal = $384,465 )
2016	2016	UNIVERSITY OF ALABAMA	P.O. BOX 870136	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	002	2	7/18/2016	SUPPLEMENT FOR EXPANSION	$68,193
2016	2016	UNIVERSITY OF ALABAMA	P.O. BOX 870136	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	2	12/11/2015	NON-COMPETING CONTINUATION	$284,644
2016	2016	UNIVERSITY OF ALABAMA	P.O. BOX 870136	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	001	2	2/5/2016	NON-COMPETING CONTINUATION	$31,628
														Subtotal = $384,465

Issue Date FY: 2015 ( Subtotal = $277,962 )
2015	2015	UNIVERSITY OF ALABAMA	P.O. BOX 870136	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	001	1	8/19/2015	SUPPLEMENT FOR EXPANSION	$16,071
2015	2015	UNIVERSITY OF ALABAMA	P.O. BOX 870136	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	1	1/6/2015	NEW	$261,891
														Subtotal = $277,962

Grand Total All Awards = $2,431,658

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Conformational dynamics and allosteric regulation during stress-responsive metallocofactor assembly

Award Number: R01GM112919

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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