Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A
Abstract Major Facilitator Superfamily Domain containing 2 A (MFSD2A) is a transporter that is highly enriched at the blood-brain and blood-retinal barriers, where it mediates Na+-dependent uptake of ω−3 fatty acids in the form of lysolipids into the brain and eyes, respectively. Despite recent stru...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39088-y |
| _version_ | 1797806605503299584 |
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| author | Shana Bergman Rosemary J. Cater Ambrose Plante Filippo Mancia George Khelashvili |
| author_facet | Shana Bergman Rosemary J. Cater Ambrose Plante Filippo Mancia George Khelashvili |
| author_sort | Shana Bergman |
| collection | DOAJ |
| description | Abstract Major Facilitator Superfamily Domain containing 2 A (MFSD2A) is a transporter that is highly enriched at the blood-brain and blood-retinal barriers, where it mediates Na+-dependent uptake of ω−3 fatty acids in the form of lysolipids into the brain and eyes, respectively. Despite recent structural insights, it remains unclear how this process is initiated, and driven by Na+. Here, we perform Molecular Dynamics simulations which demonstrate that substrates enter outward facing MFSD2A from the outer leaflet of the membrane via lateral openings between transmembrane helices 5/8 and 2/11. The substrate headgroup enters first and engages in Na+ -bridged interactions with a conserved glutamic acid, while the tail is surrounded by hydrophobic residues. This binding mode is consistent with a “trap-and-flip” mechanism and triggers transition to an occluded conformation. Furthermore, using machine learning analysis, we identify key elements that enable these transitions. These results advance our molecular understanding of the MFSD2A transport cycle. |
| first_indexed | 2024-03-13T06:09:48Z |
| format | Article |
| id | doaj.art-d3377e0f6cd442c0a87b7f58a95d4be2 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T06:09:48Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-d3377e0f6cd442c0a87b7f58a95d4be22023-06-11T11:19:45ZengNature PortfolioNature Communications2041-17232023-06-0114111510.1038/s41467-023-39088-ySubstrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2AShana Bergman0Rosemary J. Cater1Ambrose Plante2Filippo Mancia3George Khelashvili4Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell UniversityDepartment of Physiology and Cellular Biophysics, Columbia UniversityDepartment of Physiology and Biophysics, Weill Cornell Medical College, Cornell UniversityDepartment of Physiology and Cellular Biophysics, Columbia UniversityDepartment of Physiology and Biophysics, Weill Cornell Medical College, Cornell UniversityAbstract Major Facilitator Superfamily Domain containing 2 A (MFSD2A) is a transporter that is highly enriched at the blood-brain and blood-retinal barriers, where it mediates Na+-dependent uptake of ω−3 fatty acids in the form of lysolipids into the brain and eyes, respectively. Despite recent structural insights, it remains unclear how this process is initiated, and driven by Na+. Here, we perform Molecular Dynamics simulations which demonstrate that substrates enter outward facing MFSD2A from the outer leaflet of the membrane via lateral openings between transmembrane helices 5/8 and 2/11. The substrate headgroup enters first and engages in Na+ -bridged interactions with a conserved glutamic acid, while the tail is surrounded by hydrophobic residues. This binding mode is consistent with a “trap-and-flip” mechanism and triggers transition to an occluded conformation. Furthermore, using machine learning analysis, we identify key elements that enable these transitions. These results advance our molecular understanding of the MFSD2A transport cycle.https://doi.org/10.1038/s41467-023-39088-y |
| spellingShingle | Shana Bergman Rosemary J. Cater Ambrose Plante Filippo Mancia George Khelashvili Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A Nature Communications |
| title | Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A |
| title_full | Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A |
| title_fullStr | Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A |
| title_full_unstemmed | Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A |
| title_short | Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A |
| title_sort | substrate binding induced conformational transitions in the omega 3 fatty acid transporter mfsd2a |
| url | https://doi.org/10.1038/s41467-023-39088-y |
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