Browsing by Author "Pennington, Edward Ross"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation
    (Elsevier, 2018-10) Wassall, Stephen R.; Leng, Xiaoling; Canner, Samuel W.; Pennington, Edward Ross; Kinnun, Jacob J.; Cavazos, Andres T.; Dadoo, Sahil; Johnson, Dylan; Heberle, Frederick A.; Katsaras, John; Shaikh, Saame Raza; Physics, School of Science
    Docosahexaenoic acid (DHA, 22:6) is an n-3 polyunsaturated fatty acid (n-3 PUFA) that influences immunological, metabolic, and neurological responses through complex mechanisms. One structural mechanism by which DHA exerts its biological effects is through its ability to modify the physical organization of plasma membrane signaling assemblies known as sphingomyelin/cholesterol (SM/chol)-enriched lipid rafts. Here we studied how DHA acyl chains esterified in the sn-2 position of phosphatidylcholine (PC) regulate the formation of raft and non-raft domains in mixtures with SM and chol on differing size scales. Coarse grained molecular dynamics simulations showed that 1-palmitoyl-2-docosahexaenoylphosphatylcholine (PDPC) enhances segregation into domains more than the monounsaturated control, 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC). Solid state 2H NMR and neutron scattering experiments provided direct experimental evidence that substituting PDPC for POPC increases the size of raft-like domains on the nanoscale. Confocal imaging of giant unilamellar vesicles with a non-raft fluorescent probe revealed that POPC had no influence on phase separation in the presence of SM/chol whereas PDPC drove strong domain segregation. Finally, monolayer compression studies suggest that PDPC increases lipid-lipid immiscibility in the presence of SM/chol compared to POPC. Collectively, the data across model systems provide compelling support for the emerging model that DHA acyl chains of PC lipids tune the size of lipid rafts, which has potential implications for signaling networks that rely on the compartmentalization of proteins within and outside of rafts.
  • Thumbnail Image
    Item
    OxPAPC stabilizes liquid-ordered domains in biomimetic membranes
    (Elsevier BV, 2023-03) Cavazos, Andres T.; Pennington, Edward Ross; Dadoo, Sahil; Gowdy, Kymberly M.; Wassall, Stephen R.; Shaikh, Saame Raza; Physics, School of Science
    Long-chain polyunsaturated fatty acids (PUFAs) are prone to nonenzymatic oxidation in response to differing environmental stressors and endogenous cellular sources. There is increasing evidence that phospholipids containing oxidized PUFA acyl chains control the inflammatory response. However, the underlying mechanism(s) of action by which oxidized PUFAs exert their functional effects remain unclear. Herein, we tested the hypothesis that replacement of 1-palmitoyl-2-arachidonyl-phosphatidylcholine (PAPC) with oxidized 1-palmitoyl-2-arachidonyl-phosphatidylcholine (oxPAPC) regulates membrane architecture. Specifically, with solid-state 2H NMR of biomimetic membranes, we investigated how substituting oxPAPC for PAPC modulates the molecular organization of liquid-ordered (Lo) domains. 2H NMR spectra for bilayer mixtures of 1,2-dipalmitoylphosphatidylcholine-d62 (an analog of DPPC deuterated throughout sn-1 and -2 chains) and cholesterol to which PAPC or oxPAPC was added revealed that replacing PAPC with oxPAPC disrupted molecular organization, indicating that oxPAPC does not mix favorably in a tightly packed Lo phase. Furthermore, unlike PAPC, adding oxPAPC stabilized 1,2-dipalmitoylphosphatidylcholine-d6-rich/cholesterol-rich Lo domains formed in mixtures with 1,2-dioleoylphosphatidylcholine while decreasing the molecular order within 1,2-dioleoylphosphatidylcholine-rich liquid-disordered regions of the membrane. Collectively, these results suggest a mechanism in which oxPAPC stabilizes Lo domains—by disordering the surrounding liquid-disordered region. Changes in the structure, and thereby functionality, of Lo domains may underly regulation of plasma membrane-based inflammatory signaling by oxPAPC.