A Diazirine‐Modified Membrane Lipid to Study Peptide/Lipid Interactions – Chances and Challenges

The integrity of the red-cell membrane depends on molecular interactions between proteins and protein–lipid interactions: vertical interactions stabilize the membrane lipid bilayer; horizontal interactions provide resistance against shear stress. This disorder affects 1 in 25 000 individuals of northern European descent. There is typically a dominant family history, but the condition is genetically heterogeneous: combined spectrin and ankyrin deficiency is the most common defect observed, followed by band 3 deficiency, isolated spectrin deficiency, and protein 4.2 deficiency. These affect vertical membrane interactions with loss of surface area relative to red-cell volume....

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Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918387117 ◽

2020 ◽

Vol 117 (14) ◽

pp. 7803-7813 ◽

Cited By ~ 10

Author(s):

Anna L. Duncan ◽

Robin A. Corey ◽

Mark S. P. Sansom

Keyword(s):

Plasma Membrane ◽

Membrane Lipids ◽

Membrane Lipid ◽

Inward Rectifier ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Anionic Lipid ◽

Lipid Interactions ◽

Interaction Sites ◽

Lipid Species

Protein–lipid interactions are a key element of the function of many integral membrane proteins. These potential interactions should be considered alongside the complexity and diversity of membrane lipid composition. Inward rectifier potassium channel (Kir) Kir2.2 has multiple interactions with plasma membrane lipids: Phosphatidylinositol (4, 5)-bisphosphate (PIP2) activates the channel; a secondary anionic lipid site has been identified, which augments the activation by PIP2; and cholesterol inhibits the channel. Molecular dynamics simulations are used to characterize in molecular detail the protein–lipid interactions of Kir2.2 in a model of the complex plasma membrane. Kir2.2 has been simulated with multiple, functionally important lipid species. From our simulations we show that PIP2interacts most tightly at the crystallographic interaction sites, outcompeting other lipid species at this site. Phosphatidylserine (PS) interacts at the previously identified secondary anionic lipid interaction site, in a PIP2concentration-dependent manner. There is interplay between these anionic lipids: PS interactions are diminished when PIP2is not present in the membrane, underlining the need to consider multiple lipid species when investigating protein–lipid interactions.

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TMEM16 scramblases thin the membrane to enable lipid scrambling

10.21203/rs.3.rs-955726/v1 ◽

2021 ◽

Author(s):

Alessio Accardi ◽

Maria Falzone ◽

Zhang Feng ◽

Omar Alvarenga ◽

Yangang Pang ◽

...

Keyword(s):

Plasma Membrane ◽

Specific Protein ◽

Membrane Lipid ◽

Structural Requirement ◽

Lipid Asymmetry ◽

Lipid Interactions ◽

Plasma Membrane Lipid ◽

Cellular Pathways ◽

Membrane Spanning ◽

Membrane Thinning

Abstract TMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. It was proposed that lipid headgroups move between leaflets through a membrane-spanning hydrophilic groove. Direct information on lipid-groove interactions is lacking. We report the 2.3 Å resolution cryoEM structure of the Ca2+-bound afTMEM16 scramblase in nanodiscs showing how rearrangement of individual lipids at the open pathway results in pronounced membrane thinning. Only the groove’s intracellular vestibule contacts lipids, and mutagenesis suggests scrambling does not entail specific protein-lipid interactions with the extracellular vestibule. Further, we find scrambling can occur outside a closed groove in thinner membranes and is inhibited in thicker membranes despite an open pathway. Our results show how afTMEM16 thins the membrane to enable scrambling and that an open hydrophilic pathway is not a structural requirement to allow rapid transbilayer movement of lipids. This mechanism could be extended to other scramblases lacking a hydrophilic groove.

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Protein-Lipid Interactions

10.1016/s0167-7306(08)x6014-4 ◽

1993 ◽

Keyword(s):

Lipid Interactions

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Inhibition of Platelet Aggregation by Ethanol in Vitro Shows Specificity for Aggregating Agent Used and Is Influenced by Platelet Lipid Composition

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657214 ◽

1982 ◽

Vol 48 (01) ◽

pp. 049-053 ◽

Cited By ~ 47

Author(s):

C G Fenn ◽

J M Littleton

Keyword(s):

Platelet Aggregation ◽

Lipid Composition ◽

Saturated Fatty Acids ◽

Calcium Ionophore ◽

Cholesterol Content ◽

Membrane Lipid ◽

Calcium Ionophore A23187 ◽

Ionophore A23187 ◽

Increased Sensitivity

SummaryEthanol at physiologically tolerable concentrations inhibited platelet aggregation in vitro in a relatively specific way, which may be influenced by platelet membrane lipid composition. Aggregation to collagen, calcium ionophore A23187 and thrombin (low doses) were often markedly inhibited by ethanol, adrenaline and ADP responses were little affected, and aggregation to exogenous arachidonic acid was actually potentiated by ethanol. Aggregation to collagen, thrombin and A23187 was inhibited more by ethanol in platelets enriched with saturated fatty acids than in those enriched with unsaturated fats. Platelets enriched with cholesterol showed increased sensitivity to ADP, arachidonate and adrenaline but this increase in cholesterol content did not appear to influence the inhibition by ethanol of platelet responses. The results suggest that ethanol may inhibit aggregation by an effect on membrane fluidity and/or calcium mobilization resulting in decreased activity of a membrane-bound phospholipase.

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