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Construction of Model Lipid Membranes Incorporating G-protein Coupled Receptors GPCRs
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Membrane-forming phospholipids allosterically modulate native-state prolyl isomerization in a CNG channel
Ashley J Newton1, Robert D Latvala1, Adefoluke E Kuforiji1
1Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas, USA.
Protein Science : a Publication of the Protein Society
|November 20, 2025
Summary
Anionic lipids regulate the cyclic nucleotide-gated channel SthK by altering its activation and cAMP potency. These phospholipids act as allosteric regulators, influencing channel function beyond the membrane boundary.
Area of Science:
- Biochemistry
- Structural Biology
- Membrane Biophysics
Background:
- Ion channel activity is influenced by the lipid bilayer.
- Molecular mechanisms of lipid-mediated ion channel regulation are understudied.
Purpose of the Study:
- Investigate the effects of membrane-forming phospholipids on the cyclic nucleotide-gated channel SthK.
- Elucidate the molecular mechanisms of lipid-mediated allosteric regulation of SthK.
Main Methods:
- Stopped-flow flux assays to measure ion channel activity.
- Enzymatic catalysis studies to analyze protein conformational changes.
- Cryogenic electron microscopy (cryo-EM) to determine structural dynamics.
Main Results:
- Anionic lipids modulate SthK activation kinetics and cAMP potency.
- Lipids alter the cis/trans equilibrium at Pro300 in the apo state.
- Cryo-EM reveals lipid-dependent conformational changes propagating from the bundle crossing to cytosolic domains.
- Observed effects correlate with lipid headgroup electronegativity.
Conclusions:
- Membrane-forming phospholipids act as allosteric regulators of SthK.
- Lipid-mediated effects extend beyond the membrane boundary.
- Lipids control multiple functional characteristics of SthK through a common mechanism.
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