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

Autor: Wood CAP; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Zhang J; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Aydin D; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA., Xu Y; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Andreone BJ; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Langen UH; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Dror RO; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA., Gu C; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Feng L; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. liangf@stanford.edu.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. liangf@stanford.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Aug; Vol. 596 (7872), pp. 444-448. Date of Electronic Publication: 2021 Aug 04.
DOI: 10.1038/s41586-021-03782-y
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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