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

Wood CAP, Zhang J, Aydin D, Xu Y, Andreone BJ, Langen UH, Dror RO, Gu C, Feng L
Nature 596 444-448 (2021)
Cited: 35 times
EuropePMC logo PMID: 34349262

Abstract

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.

Articles - 7n98 mentioned but not cited (5)

  1. Structure and mechanism of blood-brain-barrier lipid transporter MFSD2A. Wood CAP, Zhang J, Aydin D, Xu Y, Andreone BJ, Langen UH, Dror RO, Gu C, Feng L. Nature 596 444-448 (2021)
  2. Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport. Chua GL, Tan BC, Loke RYJ, He M, Chin CF, Wong BH, Kuk ACY, Ding M, Wenk MR, Guan L, Torta F, Silver DL. Proc Natl Acad Sci U S A 120 e2215290120 (2023)
  3. Lipid flipping in the omega-3 fatty-acid transporter. Nguyen C, Lei HT, Lai LTF, Gallenito MJ, Mu X, Matthies D, Gonen T. Nat Commun 14 2571 (2023)
  4. Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A. Bergman S, Cater RJ, Plante A, Mancia F, Khelashvili G. Nat Commun 14 3391 (2023)
  5. research-article Structures of the essential efflux pump EfpA from <i>Mycobacterium tuberculosis</i> reveal the mechanisms of substrate transport and small-molecule inhibition. Wang S, Wang K, Song K, Li P, Li D, Sun Y, Mei Y, Xu C, Liao M. Res Sq rs.3.rs-3740027 (2024)


Reviews citing this publication (8)

  1. The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association. Iadecola C, Smith EE, Anrather J, Gu C, Mishra A, Misra S, Perez-Pinzon MA, Shih AY, Sorond FA, van Veluw SJ, Wellington CL, American Heart Association Stroke Council Council on Arteriosclerosis Thrombosis and Vascular Biology Council on Cardiovascular Radiology and Intervention Council on Hypertension Council on Lifestyle and Cardiometabolic Health. Stroke 54 e251-e271 (2023)
  2. Wnt Signaling in Inner Blood-Retinal Barrier Maintenance. Yemanyi F, Bora K, Blomfield AK, Wang Z, Chen J. Int J Mol Sci 22 11877 (2021)
  3. Blood-Brain Barrier Breakdown in Alzheimer's Disease: Mechanisms and Targeted Strategies. Alkhalifa AE, Al-Ghraiybah NF, Odum J, Shunnarah JG, Austin N, Kaddoumi A. Int J Mol Sci 24 16288 (2023)
  4. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)
  5. Peptides for trans-blood-brain barrier delivery. Blades R, Ittner LM, Tietz O. J Labelled Comp Radiopharm 66 237-248 (2023)
  6. The Venular Side of Cerebral Amyloid Angiopathy: Proof of Concept of a Neglected Issue. Zedde M, Grisendi I, Assenza F, Vandelli G, Napoli M, Moratti C, Lochner P, Seiffge DJ, Piazza F, Valzania F, Pascarella R. Biomedicines 11 2663 (2023)
  7. Breaking barriers in antibody discovery: harnessing divergent species for accessing difficult and conserved drug targets. Banik SSR, Kushnir N, Doranz BJ, Chambers R. MAbs 15 2273018 (2023)
  8. From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling. Briand-Mésange F, Gennero I, Salles J, Trudel S, Dahan L, Ausseil J, Payrastre B, Salles JP, Chap H. Molecules 29 3694 (2024)

Articles citing this publication (22)



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