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Membrane Protein Folding and Assembly

Award Number: R35GM139652
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: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Membrane Protein Folding and Assembly - Save date: 15 Jan 2020, 22:40 ABSTRACT Membrane Protein Folding and Assembly Many human diseases, such as cystic fibrosis, result from misfolding of membrane proteins (MPs) during their synthesis and targeting. It is therefore important to understand the principles and mechanism of MP folding and assembly. A largely unexplored part of the problem is to understand folding in the context of the cellular milieu. Toward that goal, we are studying the targeting, secretion, and insertion of membrane proteins along the so-called SecA post- translational pathway of living Escherichia coli. We have shown that the SecA motor ATPase, a significant drug target, can insert single-span membrane proteins (S-SMPs) across the E. coli inner membrane. This simplified in vivo model system eliminates the many unanswered questions about the folding of multi-span MPs along the signal recognition particle (SRP) pathway, because we gain direct access to the translocon-bilayer partitioning process. We have engineered two different chimeric protein families for probing systematically S- SMP stability using TM segments of the form GGPG-H-GPGG (used in an earlier study to determine a biological hydrophobicity scale using a cell-free eukaryotic system). To determine stabilities, we have developed methods for cleaving TM segments in vivo via native intramembrane proteases. We have discovered that many S-SMPs are stable across the membrane only because their periplasmic & cytoplasmic domains cannot cross the membrane. We have also discovered that translocon-to-membrane transfer energetics are not equal to membrane-to-cytoplasm transfer energetics and that stability depends upon growth temperature. An important aspect of our work is the use of Molecular Dynamics simulations in concert with experiments to understand the dynamics of the SecYEG translocon. Little is known about SecA function at the atomic level despite hundreds of papers on the subject. Calling upon our lab’s expertise in lipid-protein interactions, we have laid the foundation for electron cryomicroscopic (cryo-EM) studies of the structure of SecA bound to lipid nanodiscs. Our ambition is to obtain a complete structural view of the SecA-guided secretion process. SWhite_Abstract_MIRA_2020.docx, 15 January 2020


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 = $392,500 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	5	5/7/2025	NON-COMPETING CONTINUATION	$392,500
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	4	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $392,500 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	4	9/11/2024	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2023 ( Subtotal = $392,500 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	3	5/9/2023	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2022 ( Subtotal = $392,500 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	000	2	4/22/2022	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2021 ( Subtotal = $472,000 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	000	1	5/26/2021	NEW	$472,000
														Subtotal = $472,000

Grand Total All Awards = $2,042,000

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Membrane Protein Folding and Assembly

Award Number: R35GM139652

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: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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