Lipid flipping in the omega-3 fatty-acid transporter
Abstract Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-l...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37702-7 |
| _version_ | 1797822817622818816 |
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| author | Chi Nguyen Hsiang-Ting Lei Louis Tung Faat Lai Marc J. Gallenito Xuelang Mu Doreen Matthies Tamir Gonen |
| author_facet | Chi Nguyen Hsiang-Ting Lei Louis Tung Faat Lai Marc J. Gallenito Xuelang Mu Doreen Matthies Tamir Gonen |
| author_sort | Chi Nguyen |
| collection | DOAJ |
| description | Abstract Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear. Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct positions. These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease. |
| first_indexed | 2024-03-13T10:13:44Z |
| format | Article |
| id | doaj.art-91230cda4a9c49b0b4df9f927bf1cdb3 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T10:13:44Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-91230cda4a9c49b0b4df9f927bf1cdb32023-05-21T11:20:21ZengNature PortfolioNature Communications2041-17232023-05-0114111110.1038/s41467-023-37702-7Lipid flipping in the omega-3 fatty-acid transporterChi Nguyen0Hsiang-Ting Lei1Louis Tung Faat Lai2Marc J. Gallenito3Xuelang Mu4Doreen Matthies5Tamir Gonen6Howard Hughes Medical Institute, University of California Los AngelesHoward Hughes Medical Institute, University of California Los AngelesUnit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthHoward Hughes Medical Institute, University of California Los AngelesHoward Hughes Medical Institute, University of California Los AngelesJanelia Research Campus, Howard Hughes Medical InstituteHoward Hughes Medical Institute, University of California Los AngelesAbstract Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear. Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct positions. These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease.https://doi.org/10.1038/s41467-023-37702-7 |
| spellingShingle | Chi Nguyen Hsiang-Ting Lei Louis Tung Faat Lai Marc J. Gallenito Xuelang Mu Doreen Matthies Tamir Gonen Lipid flipping in the omega-3 fatty-acid transporter Nature Communications |
| title | Lipid flipping in the omega-3 fatty-acid transporter |
| title_full | Lipid flipping in the omega-3 fatty-acid transporter |
| title_fullStr | Lipid flipping in the omega-3 fatty-acid transporter |
| title_full_unstemmed | Lipid flipping in the omega-3 fatty-acid transporter |
| title_short | Lipid flipping in the omega-3 fatty-acid transporter |
| title_sort | lipid flipping in the omega 3 fatty acid transporter |
| url | https://doi.org/10.1038/s41467-023-37702-7 |
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