Caveolin assemblies displace one bilayer leaflet to organize and bend membranes DOI Creative Commons
Milka Doktorova,

Sebastian Daum,

Tyler R. Reagle

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(20)

Published: May 13, 2025

Caveolin is a monotopic integral membrane protein, widely expressed in metazoans and responsible for constructing enigmatic invaginations known as caveolae. Recently, the high-resolution structure of purified human caveolin assembly, CAV1-8S complex, revealed unique organization 11 protomers arranged tightly packed, radially symmetric spiral disc. One face outer rim this disc are hydrophobic, suggesting that complex incorporates into membranes by displacing hundreds lipids from one leaflet. The feasibility molecular architecture its biophysical functional consequences currently unknown. Using Langmuir film balance measurements, we find highly surface active, intercalating lipid monolayers various compositions. can also incorporate preformed bilayers, but only upon removal phospholipids outer-facing Atomistic coarse-grained simulations biomimetic bilayers support “leaflet replacement” model reveal accumulates 40 to 70 cholesterol molecules disordered monolayer between distal We preferentially associates with positively curved surfaces due influence on conformations leaflet lipids, these effects laterally sort lipids. Large-scale multiple assemblies confirmed their association large, morphologies consistent shape Further, regulates exposure residues implicated protein–protein interactions. Altogether, imparts unusual modes interaction implications organization, morphology, physiology.

Language: Английский

Plasma membrane transbilayer asymmetry of PI(4,5)P2drives unconventional secretion of Fibroblast Growth Factor 2 DOI Creative Commons

Manpreet Kaur,

Fabio Lolicato, Walter Nickel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 20, 2025

Summary Unconventional secretion of Fibroblast Growth Factor 2 (FGF2) is based upon direct self-translocation across the plasma membrane, a process that involves transient formation lipidic membrane pore. The opening this pore triggered by PI(4,5)P -dependent oligomerization FGF2 at inner leaflet. Subsequently, oligomers populating are captured membrane-proximal heparan sulfate chains Glypican-1 (GPC1), resulting in translocation to cell surfaces. highly negatively charged lipid exclusively localized Therefore, local accumulation leaflet produces steep and spatially restricted electrochemical gradient membrane. Furthermore, has wedge-like shape, turning it into non-bilayer destabilizes membranes high concentrations. Here we demonstrate an asymmetric distribution leaflets synthetic bilayers accelerates FGF2-induced pores. Consistently, find unconventional from cells be inhibited under conditions compromising native transbilayer asymmetry membranes. We propose lower free energy required transform bilayer proximity sites, outer could potentially repel sulfates function GPC1 extracellular space. Thus, key parameter enabling fast kinetics

Language: Английский

Citations

0
Exploring the sensitivities of experimental techniques to various types of membrane asymmetry using atomistic simulations DOI Creative Commons
Frederick A. Heberle, Milka Doktorova

Faraday Discussions, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

We use atomistic simulations of lipid bilayers to generate representative datasets from model membranes in vitro , and examine the sensitivity various experimental techniques abundance imbalances compositionally asymmetric bilayers.

Language: Английский

Citations

0
Immune cell activation produces locally scrambled foci of plasma membrane lipids DOI Creative Commons

Daryna Sputay,

Milka Doktorova, Sze Ham Chan

et al.

Faraday Discussions, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

We show that phosphatidylserine and phosphatidylethanolamine appear as transient foci on the plasma membrane external leaflet following immune receptor-mediated activation of mast cells.

Language: Английский

Citations

0
Disruption of Plasma Membrane Lipid Asymmetry Alters Cellular Energetics DOI Creative Commons
Pavel Barahtjan, Katelyn C. Cook,

Václav Bočan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Abstract Biological membranes often feature an unequal and actively maintained concentration gradients of lipids between bilayer leaflets, termed lipid asymmetry. 1–3 Lipid asymmetry has been linked to many cellular processes 4,5 , but the mechanisms that connect trans-bilayer functions are poorly understood. Here we systematically map affected by dysregulation knocking out flippases, floppases, scramblases in mammalian cells. We identify broad alterations core metabolic pathways including nutrient uptake, neutral turnover, pentose phosphate pathway glycolysis. Lipidomics, respirometry, imaging, live-cell calorimetry revealed elevated ATP consumption rates which coupled with increased heat loss per unit biomass synthesized despite slower growth. This suggests compensatory maintenance strains energy budget, inducing a shift from growth-promoting anabolic more energy-using catabolic state. Our data indicate its active is key for proper cell energetics, highlighting putative role as store potential akin proton ion transmembrane gradients.

Language: Английский

Citations

0
Caveolin assemblies displace one bilayer leaflet to organize and bend membranes DOI Creative Commons
Milka Doktorova,

Sebastian Daum,

Tyler R. Reagle

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(20)

Published: May 13, 2025

Caveolin is a monotopic integral membrane protein, widely expressed in metazoans and responsible for constructing enigmatic invaginations known as caveolae. Recently, the high-resolution structure of purified human caveolin assembly, CAV1-8S complex, revealed unique organization 11 protomers arranged tightly packed, radially symmetric spiral disc. One face outer rim this disc are hydrophobic, suggesting that complex incorporates into membranes by displacing hundreds lipids from one leaflet. The feasibility molecular architecture its biophysical functional consequences currently unknown. Using Langmuir film balance measurements, we find highly surface active, intercalating lipid monolayers various compositions. can also incorporate preformed bilayers, but only upon removal phospholipids outer-facing Atomistic coarse-grained simulations biomimetic bilayers support “leaflet replacement” model reveal accumulates 40 to 70 cholesterol molecules disordered monolayer between distal We preferentially associates with positively curved surfaces due influence on conformations leaflet lipids, these effects laterally sort lipids. Large-scale multiple assemblies confirmed their association large, morphologies consistent shape Further, regulates exposure residues implicated protein–protein interactions. Altogether, imparts unusual modes interaction implications organization, morphology, physiology.

Language: Английский

Citations

0