Open AccessStructure and mechanism of blood–brain-barrier lipid transporter MFSD2A
Author(s) -
Chase Wood,
Jinru Zhang,
Deniz Aydin,
Yan Xu,
Benjamin J. Andreone,
Urs H. Langen,
Ron O. Dror,
Chenghua Gu,
Liang Feng
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-03782-y
Subject(s) - transcytosis , symporter , blood–brain barrier , transporter , microbiology and biotechnology , mechanism (biology) , chemistry , function (biology) , biology , biophysics , biochemistry , neuroscience , gene , endocytosis , central nervous system , philosophy , epistemology , cell
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.