Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation

Stephen R. Wassall; Xiaoling Leng; Samuel W. Canner; Edward Ross Pennington; Jacob J. Kinnun; Andres T. Cavazos; Sahil Dadoo; Dylan Johnson; Frederick A. Heberle; John Katsaras; Saame Raza Shaikh

doi:10.1016/j.bbamem.2018.04.016

Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation

Stephen R. Wassall, Xiaoling Leng, Samuel W. Canner, Edward Ross Pennington, Jacob J. Kinnun, Andres T. Cavazos, Sahil Dadoo, Dylan Johnson, Frederick A. Heberle, John Katsaras, Saame Raza Shaikh

Large Scale Structures

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Abstract

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.

Original language	English
Pages (from-to)	1985-1993
Number of pages	9
Journal	Biochimica et Biophysica Acta - Biomembranes
Volume	1860
Issue number	10
DOIs	https://doi.org/10.1016/j.bbamem.2018.04.016
State	Published - Oct 2018

Funding

We thank Helgi Ingolfsson for guidance in running CG MD simulations and Bob Bittman, now sadly deceased, for PSM-d31 (NMR work). Xubo Lin gave us advice on calculating order parameters in CG simulations. The work was funded, in part, by a grant from the National Institutes of Health to S.R.S. (NIH R01AT008375). F.A.H and J.K are supported through the Scientific User Facilities Division of the Department of Energy (DOE) Office of Science, sponsored by the Basic Energy Science (BES) Program, DOE Office of Science, under contract no. DEAC05-00OR22725. A portion of this research used resources at the High Flux Isotope Reactor, a DOE Office of Science User Facility operated by the Oak Ridge National Laboratory. We thank Helgi Ingolfsson for guidance in running CG MD simulations and Bob Bittman, now sadly deceased, for PSM-d 31 (NMR work). Xubo Lin gave us advice on calculating order parameters in CG simulations. The work was funded, in part, by a grant from the National Institutes of Health to S.R.S. (NIH R01AT008375 ). F.A.H and J.K are supported through the Scientific User Facilities Division of the Department of Energy (DOE) Office of Science, sponsored by the Basic Energy Science (BES) Program, DOE Office of Science, under contract no. DEAC05-00OR22725 . A portion of this research used resources at the High Flux Isotope Reactor, a DOE Office of Science User Facility operated by the Oak Ridge National Laboratory.

Funders	Funder number
DOE Office of Science
NIH R01AT008375
S.R.S.
National Institutes of Health
U.S. Department of Energy
Office of Science
Basic Energy Sciences	BES, DEAC05-00OR22725
Basic Energy Sciences
Oak Ridge National Laboratory
National Center for Complementary and Integrative Health	R01AT008375
National Center for Complementary and Integrative Health

Keywords

Biomimetic membranes
Cholesterol
Docosahexaenoic acid (DHA)
Lipid rafts
Polyunsaturated fatty acids

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10.1016/j.bbamem.2018.04.016

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Wassall, S. R., Leng, X., Canner, S. W., Pennington, E. R., Kinnun, J. J., Cavazos, A. T., Dadoo, S., Johnson, D., Heberle, F. A., Katsaras, J., & Shaikh, S. R. (2018). Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation. Biochimica et Biophysica Acta - Biomembranes, 1860(10), 1985-1993. https://doi.org/10.1016/j.bbamem.2018.04.016

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abstract = "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.",

keywords = "Biomimetic membranes, Cholesterol, Docosahexaenoic acid (DHA), Lipid rafts, Polyunsaturated fatty acids",

author = "Wassall, {Stephen R.} and Xiaoling Leng and Canner, {Samuel W.} and Pennington, {Edward Ross} and Kinnun, {Jacob J.} and Cavazos, {Andres T.} and Sahil Dadoo and Dylan Johnson and Heberle, {Frederick A.} and John Katsaras and Shaikh, {Saame Raza}",

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Wassall, SR, Leng, X, Canner, SW, Pennington, ER, Kinnun, JJ, Cavazos, AT, Dadoo, S, Johnson, D, Heberle, FA, Katsaras, J & Shaikh, SR 2018, 'Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation', Biochimica et Biophysica Acta - Biomembranes, vol. 1860, no. 10, pp. 1985-1993. https://doi.org/10.1016/j.bbamem.2018.04.016

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T1 - Docosahexaenoic acid regulates the formation of lipid rafts

T2 - A unified view from experiment and simulation

AU - Wassall, Stephen R.

AU - Leng, Xiaoling

AU - Canner, Samuel W.

AU - Pennington, Edward Ross

AU - Kinnun, Jacob J.

AU - Cavazos, Andres T.

AU - Dadoo, Sahil

AU - Johnson, Dylan

AU - Heberle, Frederick A.

AU - Katsaras, John

AU - Shaikh, Saame Raza

PY - 2018/10

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N2 - 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.

AB - 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.

KW - Biomimetic membranes

KW - Cholesterol

KW - Docosahexaenoic acid (DHA)

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KW - Polyunsaturated fatty acids

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ER -

Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation

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