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Mechanisms of Ion Channels and Enzymatic Membrane Proteins

Award Number: R35GM131921
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: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Mechanisms of Ion Channels and Enzymatic Membrane Proteins - PROJECT SUMMARY The objectives of this research program are to understand the structural, functional, and molecular mechanisms of two classes of integral membrane proteins in eukaryotes: ion channels and enzymes that catalyze chemical reactions within lipid membranes. For ion channels, we aim to discover the mechanisms by which the channels conduct ions across cellular membranes, achieve ion selectivity, and are gated. Regarding membrane enzymes, the salient questions we will address include how both water-soluble and lipophilic substrates access membrane-embedded active sites, what underlies chemical mechanisms of catalysis, what conformational changes occur during the reaction cycles, and what constraints the lipid membrane places on these processes. We combine approaches to determine three-dimensional structures (X-ray crystallography and cryo-electron microscopy) with functional analyses (e.g. electrophysiology, enzymology, and biochemistry) to pursue holistic mechanistic understandings of these complex molecular machines. The ion channels under study include the mitochondrial calcium uniporter, the bestrophin (BEST) family of calcium-activated chloride channels, and two-pore domain potassium (K2P) channels. The mitochondrial calcium uniporter is a highly regulated multi-subunit ion channel complex. It is the primary conduit for mitochondrial calcium entry and thereby regulates ATP synthesis and other processes. Our efforts are aimed to discover the channel’s modes of ion selectivity and gating, and to investigate functions of its regulatory subunits. BEST channels form anion-selective pores that are regulated by intracellular calcium, phosphorylation, and changes in cell volume. Mutations in BEST channels cause retinal degenerative diseases. Our efforts are geared to understand the gating and selectivity properties of the channels, with particular attention to: differences among human BEST1-4 channels, interactions with binding partners (e.g. lipids and other proteins), and the possibility that the channels conduct neurotransmitters. K2P channels establish the resting potential of cells and thereby regulate immune responses and neuronal firing. We aim to determine the structures and mechanisms of the channels, with emphasis on regulation by cellular binding partners. Regarding our studies of integral membrane enzymes, current focuses are the enzymes ICMT and RCE1, which catalyze posttranslational modifications of RAS and other CAAX proteins, and the enzymes HHAT and GOAT, which attach acyl groups onto the signaling molecules Hedgehog and ghrelin. We aim to determine atomic structures of these enzymes with substrates, substrate analogs, and products that represent snapshots of their reaction coordinates – and to combine these efforts with experiments that address function. The studies will reveal principles of ion channel and enzyme function, thereby making substantial contributions to the understandings of the physiological processes that these membrane proteins control.


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 = $950,400 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	8	4/2/2026	NON-COMPETING CONTINUATION	$950,400
														Subtotal = $950,400

Issue Date FY: 2025 ( Subtotal = $950,400 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	002	7	4/10/2025	NON-COMPETING CONTINUATION	$950,400
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	6	11/21/2024	COMPETING CONTINUATION	$0
2025	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	5	2/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $950,400

Issue Date FY: 2024 ( Subtotal = $950,400 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	6	3/11/2024	COMPETING CONTINUATION	$950,400
														Subtotal = $950,400

Issue Date FY: 2023 ( Subtotal = $941,185 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	5	3/1/2023	NON-COMPETING CONTINUATION	$941,185
														Subtotal = $941,185

Issue Date FY: 2022 ( Subtotal = $941,185 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	4	3/9/2022	NON-COMPETING CONTINUATION	$847,064
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	4	6/22/2022	NON-COMPETING CONTINUATION	$94,121
														Subtotal = $941,185

Issue Date FY: 2021 ( Subtotal = $941,185 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	3	3/12/2021	NON-COMPETING CONTINUATION	$941,185
														Subtotal = $941,185

Issue Date FY: 2020 ( Subtotal = $941,185 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	2	3/19/2020	NON-COMPETING CONTINUATION	$941,185
														Subtotal = $941,185

Issue Date FY: 2019 ( Subtotal = $762,138 )
2019	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	1	3/21/2019	NEW	$762,138
														Subtotal = $762,138

Grand Total All Awards = $7,378,078

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Mechanisms of Ion Channels and Enzymatic Membrane Proteins

Award Number: R35GM131921

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: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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