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Structural mechanisms of sliding clamp loader ATPases

Award Number: R01GM127776
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: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Structural mechanisms of sliding clamp loader ATPases - Project Summary/Abstract All life forms require a ring-shaped sliding clamp to coordinate replication of their genome. These sliding clamps act as master regulators of DNA replication, coordinating replisome action with other cellular processes. These master regulators are themselves regulated by large ATPase machines called clamp loaders that either install or remove sliding clamps from DNA. This project seeks to gain an atomic-level understanding of clamp loader mechanism. These protein remodeling machines open the sliding clamp ring as a key step in their action. We have found that in the key intermediate complex—consisting of an open clamp, an ATP-bound clamp loader and the target DNA—the protein components form an open spiral that matches the helical symmetry of DNA. This symmetric spiral activates ATP hydrolysis leading to clamp closure and release of the loaded clamp. In Aim 1, we now turn our attention to the critical first two steps of the reaction: the opening of the clamp and the binding of DNA to the inner chamber of the complex. We will identify the conformational changes in the clamp loader complex that allow for opening the clamp ring, as well as how the assembly can rapidly bind a specific DNA structure in the tight confines of the complex's interior. In Aim 2, we investigate how the single subunit change in the clamp loader complex (Rfc1 replaced with Elg1) converts a dedicated clamp loader into a dedicated unloader. This work will not only reveal the mechanism and structure of a key protein involved in cancer development, but will also provide a blueprint for how an ATPase machine can be reprogrammed to perform a reverse reaction. Finally, in Aim 3 we explore how replacement of the Rfc1 subunit with the Ctf18 protein leads to an assembly that is bifunctional as both a loader and unloader, and that connects DNA replication to the process of sister chromatid cohesion. Our structures and analysis of this complex will reveal how an ATPase machine can be mechanistically flexible to catalyze both forward and reverse reactions. In addition, this work will provide insight into how this mysterious complex can link the seemingly disparate processes of DNA replication and sister chromatid cohesion. Because clamp loaders and sliding clamps are fundamental to all life, the structural insights that we obtain from completing our aims will be used for developing novel antimicrobial or chemotherapeutic drugs.


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 = -$8,503 )
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	5	5/7/2025	NON-COMPETING CONTINUATION	-$7,681
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	002	5	5/7/2025	SUPPLEMENT FOR EXPANSION	-$243
2025	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	5	5/7/2025	SUPPLEMENT FOR EXPANSION	-$579
														Subtotal = -$8,503

Issue Date FY: 2023 ( Subtotal = $393,913 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	5	2/20/2023	NON-COMPETING CONTINUATION	$35,175
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	5	1/13/2023	NON-COMPETING CONTINUATION	$316,575
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	003	5	6/12/2023	SUPPLEMENT FOR EXPANSION	$29,709
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	002	5	5/16/2023	SUPPLEMENT FOR EXPANSION	$12,454
														Subtotal = $393,913

Issue Date FY: 2022 ( Subtotal = $351,750 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	4	1/20/2022	NON-COMPETING CONTINUATION	$316,575
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	4	7/27/2022	NON-COMPETING CONTINUATION	$35,175
														Subtotal = $351,750

Issue Date FY: 2021 ( Subtotal = $351,750 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	3	1/27/2021	NON-COMPETING CONTINUATION	$316,575
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	3	3/19/2021	NON-COMPETING CONTINUATION	$35,175
														Subtotal = $351,750

Issue Date FY: 2020 ( Subtotal = $351,750 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	2	1/30/2020	NON-COMPETING CONTINUATION	$316,575
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	2	3/17/2020	NON-COMPETING CONTINUATION	$35,175
														Subtotal = $351,750

Issue Date FY: 2019 ( Subtotal = $351,750 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	1	1/24/2019	NEW	$351,750
														Subtotal = $351,750

Grand Total All Awards = $1,792,410

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Structural mechanisms of sliding clamp loader ATPases

Award Number: R01GM127776

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: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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