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Structure and mechanism of blood-brain-barrier lipid transporter MFSD2A.
Wood, Chase A P; Zhang, Jinru; Aydin, Deniz; Xu, Yan; Andreone, Benjamin J; Langen, Urs H; Dror, Ron O; Gu, Chenghua; Feng, Liang.
Afiliación
  • 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.
  • Xu Y; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • Andreone BJ; Department of Computer Science, Stanford University, Stanford, CA, USA.
  • Langen UH; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
  • Dror RO; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • Gu C; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
  • Feng L; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Nature ; 596(7872): 444-448, 2021 08.
Article en En | MEDLINE | ID: mdl-34349262
MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain1,2, which is crucial for the development and performance of the brain3. Mutations that affect MFSD2A cause microcephaly syndromes4,5. 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 barrier6,7. 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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Simportadores / Metabolismo de los Lípidos Límite: Animals / Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Simportadores / Metabolismo de los Lípidos Límite: Animals / Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos