ArticleThe Journal of biological chemistry2016
Structural Insights into the Transport Mechanism of the Human Sodium-dependent Lysophosphatidylcholine Transporter MFSD2A.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 74 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- MFSD2A in health and disease: lysolipid transport, barrier physiology, and translational boundaries.Molecular biomedicine · 2026Review
- From Dysbiosis to Blood-Brain Barrier Disruption: The Metabolite-Mediated Gut-Brain Axis in Alzheimer's Disease.Molecular neurobiology · 2026Review
- In vitro Reconstitution of Syncytin-2 and MFSD2A Reveals their Functional Tethering in Membrane Fusion Initiation.The Journal of membrane biology · 2026Article
- DHA: Nutritional Programming During the First 1000 Days of Life.Nutrients · 2026Review
- Liver transcriptome dynamics in Holstein cows during the periparturient transition.Scientific reports · 2026Article
- Mfsd2a is important for maintaining epidermal homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- L-Borneolum Attenuates Ischemic Stroke Through Remodeling BBB Transporter Function via Regulating MFSD2A/Cav-1 Signaling Pathway.Brain sciences · 2026Article
- MFSD2A: a molecular nexus linking blood-brain barrier, lipid metabolism, and ischemia-reperfusion injury.Cellular & molecular biology letters · 2025Review
- MFSD2A in Focus: the Molecular Mechanism of Omega-3 Fatty Acid Transport.Physiology (Bethesda, Md.) · 2025Review
- Cellular and organismal function of choline metabolism.Nature metabolism · 2025Review
- Novel approach to enhancing brain DHA uptake: the role of nannochloropsis microalgae extract.Frontiers in nutrition · 2025Article
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- Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition.The Journal of clinical investigation · 2023Article
- Structural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate.Cell · 2023Article
- Lipid flipping in the omega-3 fatty-acid transporter.Nature communications · 2023Article
- Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Esterification of Docosahexaenoic Acid Enhances Its Transport to the Brain and Its Potential Therapeutic Use in Brain Diseases.Nutrients · 2022Review
- Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Major facilitator superfamily domain containing 2A (MFSD2A) was recently characterized as a sodium-dependent lysophosphatidylcholine transporter expressed at the blood-brain barrier endothelium. It is the primary route for importation of docosohexaenoic acid and other long-chain fatty acids into fetal and adult brain and is essential for mouse and human brain growth and function. Remarkably, MFSD2A is the first identified major facilitator superfamily member that uniquely transports lipids, implying that MFSD2A harbors unique structural features and transport mechanism. Here, we present three three-dimensional structural models of human MFSD2A derived by homology modeling using MelB- and LacY-based crystal structures and refined by biochemical analysis. All models revealed 12 transmembrane helices and connecting loops and represented the partially outward-open, outward-partially occluded, and inward-open states of the transport cycle. In addition to a conserved sodium-binding site, three unique structural features were identified as follows: a phosphate headgroup binding site, a hydrophobic cleft to accommodate a hydrophobic hydrocarbon tail, and three sets of ionic locks that stabilize the outward-open conformation. Ligand docking studies and biochemical assays identified Lys-436 as a key residue for transport. It is seen forming a salt bridge with the negative charge on the phosphate headgroup. Importantly, MFSD2A transported structurally related acylcarnitines but not a lysolipid without a negative charge, demonstrating the necessity of a negatively charged headgroup interaction with Lys-436 for transport. These findings support a novel transport mechanism by which lysophosphatidylcholines are "flipped" within the transporter cavity by pivoting about Lys-436 leading to net transport from the outer to the inner leaflet of the plasma membrane.
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