![]() ![]() ![]() ![]() Fine structural localization of a blood-brain barrier to exogenous peroxidase. ![]() Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Mfsd2a is critical for the formation and function of the blood-brain barrier. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Health benefits of docosahexaenoic acid (DHA). Structural insights into the transport mechanism of the human sodium-dependent lysophosphatidylcholine transporter MFSD2A. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. These results shed light on the critical lipid transport function of MFSD2A and provide a framework to aid in the design of specific modulators for therapeutic purposes. The structure-together with our functional studies and molecular dynamics simulations-identifies a conserved sodium-binding site, reveals a potential lipid entry pathway and helps to rationalize MFSD2A mutations that underlie microcephaly syndromes. Our structure defines the architecture of this important transporter, reveals its unique extracellular domain and uncovers its substrate-binding cavity. Here we report the cryo-electron microscopy structure of mouse MFSD2A. Thus, MFSD2A represents an attractive target for modulating the permeability of the blood–brain barrier for drug delivery. The ability of MFSD2A to transport lipid is also a key mechanism that underlies its function as an inhibitor of transcytosis to regulate the blood–brain barrier 6, 7. Mutations that affect MFSD2A cause microcephaly syndromes 4, 5. MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain 1, 2, which is crucial for the development and performance of the brain 3. ![]()
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