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PreprintCited by 45Drug Transport and Resistance MechanismsBarrier Structure and Function StudiesAmino Acid Enzymes and Metabolism

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Structural and molecular basis of choline uptake into the brain by FLVCR2

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Cater, Rosemary J., Mukherjee, Dibyanti, Iturbe, Eva Gil, Erramilli, Satchal K., Chen, Ting, Koo, Katie, Grez, Nicolás Santander, Reckers, Andrew, Kloss, Brian, Gawda, Tomasz, Choy, Brendon C., Zheng, Zhening, Clarke, Oliver B., Yee, Sook Wah, Kossiakoff, Anthony A., Quick, Matthias, Arnold, Thomas, Mancia, Filippo·2023·Nature
DOI 10.1101/2023.10.05.561059PMC PMC11168207

Preprint — published as 10.1038/s41586-024-07326-y · Paper page

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Abstract

Choline is an essential nutrient that the human body needs in vast quantities for cell membrane synthesis, epigenetic modification, and neurotransmission. The brain has a particularly high demand for choline, but how it enters the brain has eluded the field for over fifty years. The MFS transporter FLVCR1 was recently determined to be a choline transporter, and while this protein is not highly expressed at the blood-brain barrier (BBB), its relative FLVCR2 is. Previous studies have shown that mutations in human Flvcr2 cause cerebral vascular abnormalities, hydrocephalus, and embryonic lethality, but the physiological role of FLVCR2 is unknown. Here, we demonstrate both in vivo and in vitro that FLVCR2 is a BBB choline transporter and is responsible for the majority of choline uptake into the brain. We also determine the structures of choline-bound FLVCR2 in the inward- and outward-facing states using cryo-electron microscopy to 2.49 and 2.77 Å resolution, respectively. These results reveal how the brain obtains choline and provide molecular-level insights into how FLVCR2 binds choline in an aromatic cage and mediates its uptake. Our work could provide a novel framework for the targeted delivery of neurotherapeutics into the brain.

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Research works printed but not linked: 54

  1. 10.1111/j.1753-4887.2009.00246.x · DOI · Paper page
  2. 10.1146/annurev.nutr.26.061505.111156 · DOI · Paper page
  3. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. (National Academies Press (US), 1998).
  4. 10.1002/iub.337 · DOI
  5. 10.1007/s10545-010-9088-4 · DOI
  6. 10.1016/j.jnutbio.2012.03.003 · DOI
  7. 10.1001/archneur.1971.00480340065007 · DOI
  8. 10.1016/j.neuint.2015.12.011 · DOI
  9. 2023, The cellular supply-side economics for phospholipids, Cell Metabolism, 35, 909, 10.1016/j.cmet.2023.05.004 · DOI
  10. 10.1523/JNEUROSCI.1860-14.2014 · DOI · Paper page
  11. 10.1016/j.neuron.2015.11.013 · DOI · Paper page
  12. 2023, Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals, Cell Metabolism, 35, 1057, 10.1016/j.cmet.2023.04.003 · DOI
  13. 2023, Organelle-selective click labeling coupled with flow cytometry allows pooled CRISPR screening of genes involved in phosphatidylcholine metabolism, Cell Metabolism, 35, 1072, 10.1016/j.cmet.2023.02.014 · DOI
  14. 10.1023/A:1022809003997 · DOI
  15. 10.1126/scisignal.aag2476 · DOI
  16. 10.1172/JCI136578 · DOI
  17. 10.1016/j.ajhg.2010.02.004 · DOI
  18. Kalailingam, P. et al. Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome. The Journal of clinical investigation 130, (2020). · DOI
  19. 10.1073/pnas.0609573104 · DOI
  20. 10.1016/j.tibs.2013.01.003 · DOI
  21. 10.1076/apab.110.5.393.11832 · DOI
  22. 1984, The kinetic mechanism by which CCCP (carbonyl cyanidem-Chlorophenylhydrazone) transports protons across membranes, J. Membrain Biol, 82, 179, 10.1007/BF01868942 · DOI · Paper page
  23. 2020, A 10-year meta-analysis of membrane protein structural biology: Detergents, membrane mimetics, and structure determination techniques, Biochim Biophys Acta Biomembr, 1863, 183533
  24. 10.1016/j.str.2015.11.014 · DOI
  25. 10.1016/bs.mie.2014.12.032 · DOI
  26. 10.1073/pnas.0401786101 · DOI
  27. 10.1016/j.sbi.2020.05.009 · DOI
  28. 2022, Putting on molecular weight: Enabling cryo-EM structure determination of sub-100-kDa proteins, Current Research in Structural Biology, 4, 332, 10.1016/j.crstbi.2022.09.005 · DOI
  29. 10.1126/sciadv.abm1122 · DOI
  30. 10.1016/j.sbi.2016.10.018 · DOI
  31. 10.1038/s41594-023-01039-y · DOI
  32. 10.1073/pnas.0914328107 · DOI
  33. 10.1096/fj.15-282426 · DOI
  34. 10.1038/s41467-020-18607-1 · DOI
  35. 2012, Tools for coproducing multiple proteins in mammalian cells, Methods Mol Biol, 801, 173, 10.1007/978-1-61779-352-3_12 · DOI
  36. 10.1016/j.str.2006.01.013 · DOI
  37. 10.1172/JCI136578 · DOI
  38. Kalailingam, P. et al. Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome. The Journal of clinical investigation 130, (2020). · DOI
  39. 10.1093/nar/18.20.6069 · DOI
  40. 10.1038/msb.2011.75 · DOI
  41. 1995, Reconstitution of membrane proteins into liposomes: application to energy-transducing membrane proteins, Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1231, 223, 10.1016/0005-2728(95)00091-V · DOI
  42. 10.1371/journal.pone.0043746 · DOI
  43. 2021, Structural basis of omega-3 fatty acid transport across the blood-brain barrier, Nature, 595, 315, 10.1038/s41586-021-03650-9 · DOI
  44. 10.1038/s41586-019-1795-x · DOI
  45. 10.1074/jbc.RA117.000656 · DOI
  46. 10.1016/j.jsb.2005.03.010 · DOI
  47. 10.1038/nmeth.4169 · DOI · Paper page
  48. 2019, Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs, Nat Methods, 16, 1153, 10.1038/s41592-019-0575-8 · DOI
  49. 10.1002/jcc.20084 · DOI
  50. 10.1107/S0907444904019158 · DOI · Paper page
  51. 10.1107/S0907444910007493 · DOI · Paper page
  52. 10.1107/S0907444909052925 · DOI · Paper page
  53. 10.1073/pnas.0811322106 · DOI
  54. 10.1038/nmeth.4169 · DOI · Paper page

Metadata

Authors
Cater, R. J., Mukherjee, D., Iturbe, E. G., Erramilli, S. K., Chen, T., Koo, K., Grez, N. S., Reckers, A., Kloss, B., Gawda, T., Choy, B. C., Zheng, Z., Clarke, O. B., Yee, S. W., Kossiakoff, A. A., Quick, M., Arnold, T., & Mancia, F.
Affiliations
  • The University of Queensland (AU)
  • University of California, San Francisco (US)
  • University of Chicago (US)
  • Columbia University (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
  • Cater, Rosemary J.
  • Arnold, Thomas
  • Mancia, Filippo
ORCID
Venue
Nature
Publisher
openRxiv
Published
2023-10-05
Volume
629
Issue
8012
Pages
704-709
ISSN
0028-0836 (ISSN-L)
DOI
10.1101/2023.10.05.561059
PMC
PMC11168207
OpenAlex
W4396544306
Cited by
45
References
1
Citations by year
2026: 18 · 2025: 20 · 2024: 7
FWCI
7.71
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (GM116799)
  • Australian Research Council (DE230101536)
  • National Heart, Lung, and Blood Institute (K99HL166866)
  • National Institute of General Medical Sciences (P41GM116799, R01GM117372, R35GM132120)
  • National Institute of Neurological Disorders and Stroke (R21NS129105, R01NS142590, R01NS123168)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
choline uptake, blood-brain barrier, choline transporter, major facilitator superfamily, endothelial cells, transporter structure, aromatic cage, cerebral vascular abnormalities, hydrocephalus

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