Membrane curvature and PS localize coagulation proteins to filopodia and retraction fibers of endothelial cells, 2022, Carman et al

[Andy]

Key Points

• Convex membrane curvature and phosphatidylserine create discreet binding locations for lactadherin and coagulation factor V(a)
  
  
• Stressed endothelial cells extend filaments with both high convexity and PS, establishing discreet sites of prothrombinase activity
  

Prior reports indicate that convex membrane curvature of phosphatidylserine (PS)-containing vesicles enhances formation of binding sites for factor Va and lactadherin. Yet, the relationship of convex curvature to localization of these proteins on cells remains unknown.

We developed a membrane topology model, utilizing phospholipid bilayers supported by nano-etched silica substrates, to further explore the relationship between curvature and localization of coagulation proteins. Ridge convexity corresponded to maximal curvature of physiologic membranes (radii of 10 or 30 nm) and troughs had variable concave curvature. The benchmark PS probe, lactadherin, exhibited strong differential binding to the ridges, on membranes with 4-15% PS. Factor Va, with a PS-binding motif homologous to lactadherin, also bound selectively to the ridges. Bound factor Va supported coincident binding of factor Xa, localizing prothrombinase complexes to ridges. Endothelial cells responded to pro-thrombotic stressors and stimuli (staurosporine, TNF-) by retracting cell margins, forming filaments and filopodia. These had high positive curvature similar to supported membrane ridges and selectively bound lactadherin. Likewise, the retraction filaments and filopodia bound factor Va and supported assembly of prothrombinase while the cell body did not.

Perfusion of plasma over TNF--stimulated endothelia in culture dishes and engineered 3D microvessels led to fibrin deposition at cell margins, inhibited by lactadherin, without clotting of bulk plasma. Our results indicate that stressed or stimulated endothelial cells support prothrombinase activity localized to convex topological features at cell margins. These findings may relate to perivascular fibrin deposition in sepsis and inflammation.

Open access, https://ashpublications.org/bloodad...embrane-curvature-and-PS-localize-coagulation

 

[boolybooly]

I wonder if membrane topology and flexibility would account for the proinflammatory effects of medium chain triglycerides (MCTs) observed in this paper.

"Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563838/?report=classic

MCT suppressed antigen absorption into blood, but stimulated absorption into Peyer's patches. ...
Conclusion : Dietary MCT promote allergic sensitization and anaphylaxis by affecting antigen absorption and availability and by stimulating Th2 responses.

Absorption of antigens in Peyer's patches begins with microfold or M-cells, so called because of the topology of their gut facing membrane which, where not showing microvilli, shows microfolds on the surface, i.e. a specific convex+concave topology associated with the task of binding and transporting antigens.
https://en.wikipedia.org/wiki/Peyer's_patch
https://en.wikipedia.org/wiki/Microfold_cell

EDIT - to be specific,

• it strikes me that the composition of the membrane bilayer might effect the radius of curvature and thus the spacing of the receptors on the outer surface. A shorter lipid molecule array can adopt a tighter radius of curvature due to the geometry of the molecules.
• It is also possible that the density of the membrane bilayer relative to the forces holding it together might have an effect on kinetics of molecular transport.
• In addition the cohesion and lability of the membrane due to Van der Waals forces may change depending on the length of the constituent lipid molecules interacting between themselves and through hydrophilic moieties in relation to external media of aqueous ionic solutions, through the leverage imposed on the molecules by these forces. Shorter molecules like MCTs have less hydrophobic tail and this may make any membrane of which they are a major constituent more labile effecting the kinetics of antigen transfer by reducing the activation energy required to induce antigen transfer across the membrane.

/my two cents


I ask because I believe I have been able to reduce excessive inflammatory symptoms by changing my dietary lipid intake, specifically eliminating MCTs and I wonder if this approach has a broader therapeutic potential but I have not seen a lot of studies in this area.