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Native ion mobility mass spectrometry studies of potassium inward rectifier channels: insight into gating and lipid binding

Award Number: DP2GM123486
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Membrane proteins are embedded in the biological membrane where they function and intimately interact with lipid molecules. The environment of the biological membrane is dynamic and composed of a rich chemical diversity of lipid molecules. Alongside the complexity of the biological membrane is the growing realization of the important roles of lipid molecules in the folding, structure, and function of membrane proteins. In particular, inward rectifier potassium (Kir) channels have central roles in regulating membrane potential and potassium homeostasis. It has been known for nearly 20 years that these channels require a specific lipid for function. Although many studies have provided insight into Kir channel structure and function, there remain a number of fundamental questions: What determines the selectivity of Kir channels towards lipids? What are the thermodynamic binding parameters for individual lipid binding events to Kir channels? Do lipids bind cooperatively to Kir channels? Does Kir channel conformation (open or closed) influence the selectivity towards individual lipids? How many specific lipids are required to gate Kir channels? What are the thermodynamic stabilities of Kir channel open and closed states when bound to one, two, three, or four specific lipids? Here, we propose to address these fundamental questions using native ion mobility mass spectrometry (IM-MS) technology, whereby non-covalent interactions are preserved in the mass spectrometer and capitalize on IM-MS approaches we have pioneered that, unlike other biophysical methods, allow us to resolve and interrogate individual lipid binding events to membrane protein complexes. We seek to apply novel and highly innovative IM-MS approaches that we have recently developed to deduce thermodynamic binding parameters for individual lipid binding events to membrane proteins. Moreover, we propose to investigate Kir channel gating using IM-MS that will allow us for the first time to monitor the conformational states (open and closed) for apo and lipid bound states. Our proposal will also investigate the allosteric regulation of Kir channels by lipids and other molecules using new IM-MS methods we have recently developed to resolve and interrogate heterogeneous lipid binding events at the resolution of individual lipids. Taken together, we anticipate the results from our proposed studies to provide fundamental insight into how lipids and other molecules modulate the structure and function of Kir channels.


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: 2021 ( Subtotal = -$100,964 )
2021	2016	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	2	3/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2016	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	001	2	9/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$100,964
														Subtotal = -$100,964

Issue Date FY: 2018 ( Subtotal = -$1 )
2018	2016	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	11/11/2017	NEW	-$1
														Subtotal = -$1

Issue Date FY: 2017 ( Subtotal = $1 )
2017	2016	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	8/1/2017	NEW	-$2,213,980
2017	2016	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	001	2	8/2/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,213,981
														Subtotal = $1

Issue Date FY: 2016 ( Subtotal = $2,227,500 )
2016	2016	TEXAS A&M UNIVERSITY HEALTH SCIENCE CENTER	301 Tarrow	COLLEGE STATION	TX	77840	BRAZOS	USA	Biomedical Research and Research Training	000	1	9/20/2016	NEW	$2,227,500
														Subtotal = $2,227,500

Grand Total All Awards = $2,126,536

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Native ion mobility mass spectrometry studies of potassium inward rectifier channels: insight into gating and lipid binding

Award Number: DP2GM123486

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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