Thursday, September 18, 2025 9/18/2025

Dynamics of lipid-anchored proteins

Award Number: R01GM144836
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Dynamics of lipid-anchored proteins - It is often assumed that lipid-anchored proteins non-specifically attach to membranes by the hydrophobic lipid- modified moiety. We propose that it takes more than lipid-modification to productively organize lipid-anchored proteins on target membranes. We will test this hypothesis using the Ras superfamily of lipid-anchored small GTPases (laSGs) as model systems. The Ras superfamily consists of the Ras, Rho, Arf and Rab family of molecular switches that mediate a wide variety of cellular processes controlling cell growth, motility and trafficking. The structure of these proteins consists of a conserved catalytic domain, a flexible linker, and a lipid anchor. Little is known about the precise roles of the intrinsically disordered linker region. By contrast, it is well established that cycling between active GTP-bound and inactive GDP-bound conformational states of the catalytic domain regulate function. Disruption of this cycle by mutation or genetic defects causes many diseases including cancer and developmental disorders. The proposed work will lay the foundation for the development of effective therapies that directly target these proteins. Supported by strong preliminary data, we hypothesize that monomeric laSGs engage membranes through one of the following mechanisms: (i) Those with a moderately long (~20aa) flexible linker between the lipid-anchor and the G-domain adopt multiple distinct orientations with respect to the membrane plane, with the catalytic domain ‘swinging’ and ‘rolling’ on the surface. (ii) Those with a long flexible linker keep the G-domain distal from the membrane, with the long linker collapsing on it as spaghetti would on a wall. (iii) Those with a short (and rigid) linker, such as GTP-bound Arf1, engage membranes in a single orientation with the G-domain able to roll but not swing on the membrane surface. (iv) The G-domain of dually lipid-anchored laSGs does not reorient. We will test these hypotheses using state-of- the-art molecular simulations and simulation-guided experiments. In Aim 1 we will define the sequence and structural determinants of membrane binding and reorientation of laSGs using atomistic molecular dynamics simulations to map the conformational and energy landscapes of Rheb, RhoA, Rab11A and Arf1, representing the Ras, Rho, Rab and Arf family proteins, respectively. In Aim 2, we will determine the functional roles of G- domain membrane engagement and reorientation using mutations and cell signaling assays, confocal imaging, electron microscopy (EM), and single molecule FRET in native lipid nanodiscs. Aim 3 will assess the impact of G-domain membrane interaction and reorientation on the druggability of our model systems. The results will elucidate the principles and structural regions responsible for the dynamic membrane interaction of laSGs and define the determinants of their membrane reorientation, and potentially open up novel therapeutic opportunities to treat many intractable diseases.


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 = $311,999 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	4	8/13/2025	NON-COMPETING CONTINUATION	$31,200
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	4	11/20/2024	NON-COMPETING CONTINUATION	$280,799
														Subtotal = $311,999

Issue Date FY: 2024 ( Subtotal = $311,999 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	3	6/11/2024	NON-COMPETING CONTINUATION	$31,200
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	3	12/4/2023	NON-COMPETING CONTINUATION	$280,799
														Subtotal = $311,999

Issue Date FY: 2023 ( Subtotal = $510,275 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	001	2	4/5/2023	NON-COMPETING CONTINUATION	$31,200
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	002	2	6/7/2023	SUPPLEMENT FOR EXPANSION	$198,276
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	2	12/8/2022	NON-COMPETING CONTINUATION	$280,799
														Subtotal = $510,275

Issue Date FY: 2022 ( Subtotal = $311,999 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	1	11/29/2021	NEW	$311,999
														Subtotal = $311,999

Grand Total All Awards = $1,446,272

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Dynamics of lipid-anchored proteins

Award Number: R01GM144836

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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