Pharmacological tools to modulate ordered membrane domains and order-dependent protein function
Year: 2026
Type: article
Abstract: Ordered membrane nanodomains colloquially known as “lipid rafts” have many proposed cellular functions. However, pharmacological tools to modulate protein affinity for rafts and to manipulate raft formation are currently lacking. We screened 24,000 small molecules for compounds that impact the raft affinity of a known raft-preferring protein, peripheral myelin protein 22 (PMP22), in giant plasma membrane vesicles (GPMVs). Hits were counter-screened against another raft protein, MAL, and also tested for their impact on raft stability. We identified three chemically distinct tools for manipulating lipid rafts. Two compounds were seen to both decrease PMP22 raft partitioning and to destabilize ordered domains (VU0607402 and VU0519975) while a third (primaquine diphosphate) increased PMP22 partitioning and stabilized ordered domains. While discovered in a PMP22-focused screen, all three were seen to modulate raft formation in a protein-independent manner by altering lipid-lipid interactions and membrane fluidity. Acute treatment of live cells with the raft destabilizing compound, VU0607402 was seen to modulate TRPM8 channel function, highlighting the utility of this compound in live-cell experiments for dissecting the role that membrane order and fluidity play in cell signaling. These compounds provide novel pharmacological tools for probing lipid raft properties and function in biophysical experiments and in living cells.
Source: Communications Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: Vanderbilt University, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Vanderbilt Institute of Chemical Biology, School of Medicine, Vanderbilt University
Awards: G1149166549, Advancing Opportunities for Ped. Research and the Role of CC-CHOC within NCATS, G2268269956, G2515486903, G3433274139, G35732448, G3846763807, G3865556588, Vanderbilt Mouse Metabolic Phenotyping Center, G4320917349, G4379182500, LSM880-Airyscan Confocal Microscope for Large Shared Resource, Automated Compound Storage and Retrieval System, G5853943267, G6940670348, G7220527126, G7520984233, Small Molecule Tools for Modulating Membrane Rafts, Integrated ImageXpress Micro Confocal High Content Screening System, Linking Clinical Translational Science Award Sites to Improve Pediatric Research, G8370102485, Studying EGFR where it lives: How membrane lipids define receptor properties, G9000002043, G9000060478, G9000064184, G9000076948, G9000081609, G9000083539, G9000089795, G9000106052, G9000122305, G9000159340, Molecular and Cellular Basis for Digestive Diseases, Cancer Pharmacologist and HTS Scientist, Vanderbilt Diabetes Research Center, Decrypting Variants of Uncertain Significance in Long-QT Syndrome, Core Grant in Vision Research, Molecular Mechanisms and Regulation Networks of TRPM8
OpenAlex ID: W7119464959