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Structure and function of the Plasmodium myosin XIV-actin glideosome.

Award Number: R01AI132378
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/11/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Structure and function of the Plasmodium myosin XIV-actin glideosome. - Malaria infection in humans, caused by single-celled parasites from the genus Plasmodium, is a major global health challenge. Despite marked progress in the last 15 years, more than 400 million deaths occur worldwide annually, the majority being children under age 5. Recent licensure of the first ever malaria vaccine heralds a new era in efforts to control malaria, but the relatively modest efficacy of the RTS,S vaccine means that complementary approaches will be essential if the WHO's goal of a 90% reduction in rates by 2030 is to be realized. Malaria parasites are motile throughout their complex human and mosquito lifecycle. They move by a process called gliding motility, which underpins their ability to reach, cross, and enter host tissues and cells. Gliding is powered by a parasite actomyosin motor the disruption of which kills the infectious parasite. Towards development of the parasite actomyosin motor as a druggable target, our collaborative team has worked to characterize the essential class XIV single-headed myosin motor PfMyoA, the core of gliding motility. We were the first to characterize and crystallize PfMyoA, demonstrating that its function is uniquely tuned by N-terminal heavy chain phosphorylation. We were the first to show the essential role of PfMyoA and its essential light chain in powering red blood cell (RBC) invasion, the stage responsible for all malaria pathogenesis. We have since used PfMyoA mutants to reveal the energetic barriers necessary for RBC invasion using live cell imaging. These foundations expertly position our team to extend investigation of gliding motility across the malaria lifecycle and explore additional Plasmodium myosins and their cellular roles, which are the combined aims of this competitive renewal. We propose (Aim 1) to define the cellular roles of PfMyoB versus PfMyoA by comparing structures, functional properties, and the role of heavy chain phosphorylation in vitro and in vivo. Aim 2 proposes to determine the binding pocket, mechanism of action, and impact on the parasite of two first-in-class small molecule inhibitors of PfMyoA ATPase activity. Aim 3 investigates two other essential Plasmodium myosins (PfMyoF and K), which are virtually unstudied both as motors and potential future druggable targets. PfMyoF likely plays a role as a processive transporter, while PfMyoK likely functions during sexual development, with motor domain inserts typical of reverse-directionality in eukaryotic class VI motors. We will use an integrative approach highlighting in vitro functional assays (motility and ensemble force assays, optical trap assays, steady- state and transient kinetics) and structural studies (X-ray crystallography and cryo-EM) together with live cell approaches (including super resolution imaging) and genetic investigation of motors (conditional knockouts/substitutions) in several stages of the Plasmodium parasite lifecycle. At completion we will have developed a previously unattainable depth of understanding into the function of the essential Plasmodium myosins as druggable targets, revealed profound insights into the structural basis by which myosins produce force and motion, and discovered fundamental insights into malaria parasite cell biology.


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: 2026 ( Subtotal = $661,630 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	10	6/30/2026	NON-COMPETING CONTINUATION	$661,630
														Subtotal = $661,630

Issue Date FY: 2025 ( Subtotal = $661,630 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	9	9/9/2025	NON-COMPETING CONTINUATION	$661,630
														Subtotal = $661,630

Issue Date FY: 2024 ( Subtotal = $661,630 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	002	8	6/18/2024	NON-COMPETING CONTINUATION	$661,630
2024	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	6	10/17/2023	COMPETING CONTINUATION	$83,971
2024	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	5	10/17/2023	NON-COMPETING CONTINUATION	-$83,971
														Subtotal = $661,630

Issue Date FY: 2023 ( Subtotal = $661,630 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	7	6/21/2023	NON-COMPETING CONTINUATION	$661,630
2023	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	5	6/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $661,630

Issue Date FY: 2022 ( Subtotal = $689,630 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	6	6/21/2022	COMPETING CONTINUATION	$689,630
2022	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	5	6/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $689,630

Issue Date FY: 2021 ( Subtotal = $710,260 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	5	9/16/2021	NON-COMPETING CONTINUATION	$710,260
2021	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	4	11/25/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $710,260

Issue Date FY: 2020 ( Subtotal = $710,260 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	4	4/30/2020	NON-COMPETING CONTINUATION	$710,260
														Subtotal = $710,260

Issue Date FY: 2019 ( Subtotal = $710,260 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	3	4/11/2019	NON-COMPETING CONTINUATION	$710,260
														Subtotal = $710,260

Issue Date FY: 2018 ( Subtotal = $710,260 )
2018	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	2	4/11/2018	NON-COMPETING CONTINUATION	$710,260
														Subtotal = $710,260

Issue Date FY: 2017 ( Subtotal = $737,484 )
2017	2017	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	1	5/10/2017	NEW	$737,484
														Subtotal = $737,484

Grand Total All Awards = $6,914,674

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Structure and function of the Plasmodium myosin XIV-actin glideosome.

Award Number: R01AI132378

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/11/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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