Structure and mechanism of blood–brain-barrier lipid transporter MFSD2A

• Published in: Nature (London) Vol. 596; no. 7872; pp. 444 - 448
• Main Authors: Wood, Chase A. P., Zhang, Jinru, Aydin, Deniz, Xu, Yan, Andreone, Benjamin J., Langen, Urs H., Dror, Ron O., Gu, Chenghua, Feng, Liang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.08.2021; Nature Publishing Group
• Subjects: 101/28; 631/378/1341; 631/535/1258/1259; 631/92/577; 82; 82/16; 82/80; 82/83; Animals; Binding Sites; Biological Transport; Blood-brain barrier; Blood-Brain Barrier - metabolism; Carrier proteins; Disorders; Docosahexaenoic acid; Drug delivery; Dynamic structural analysis; Electron microscopy; Health aspects; HEK293 Cells; Humanities and Social Sciences; Humans; Lipid Metabolism; Lipids; Lysophosphatidylcholine; Membrane permeability; Mice; Microcephaly; Microscopy; Models, Molecular; Modulators; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Mutagenesis; Mutation; Permeability; Physiological aspects; Protein Domains; Science; Science (multidisciplinary); Simulation; Sodium; Sodium - metabolism; Structure; Substrates; Symporters - chemistry; Symporters - genetics; Symporters - metabolism; Symporters - ultrastructure; Therapeutic applications; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03782-y

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 . Mutations that affect MFSD2A cause microcephaly syndromes 4 , 5 . 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 . Thus, MFSD2A represents an attractive target for modulating the permeability of the blood–brain barrier for drug delivery. Here we report the cryo-electron microscopy structure of mouse MFSD2A. Our structure defines the architecture of this important transporter, reveals its unique extracellular domain and uncovers its substrate-binding cavity. 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. 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 cryo-electron microscopy structure of mouse MFSD2A sheds light on the mechanism that underlies its lipid transport functions, which have a pivotal role in regulating the blood–brain barrier.