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

Autor: Cater RJ; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. r.cater@uq.edu.au.; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia. r.cater@uq.edu.au., Mukherjee D; Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA., Gil-Iturbe E; Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA., Erramilli SK; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA., Chen T; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA., Koo K; Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA., Santander N; Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile., Reckers A; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Kloss B; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA., Gawda T; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA., Choy BC; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA., Zhang Z; Cryo-Electron Microscopy Center, Columbia University, New York, NY, USA., Katewa A; Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA., Larpthaveesarp A; Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA., Huang EJ; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.; Pathology Service, San Francisco VA Medical Center, San Francisco, CA, USA., Mooney SWJ; Burke Neurological Institute, White Plains, NY, USA., Clarke OB; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.; Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA., Yee SW; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA., Giacomini KM; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA., Kossiakoff AA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA., Quick M; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.; Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.; New York State Psychiatric Institute, Area Neuroscience-Molecular Therapeutics, New York, NY, USA., Arnold T; Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA. thomas.arnold@ucsf.edu., Mancia F; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. fm123@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 May; Vol. 629 (8012), pp. 704-709. Date of Electronic Publication: 2024 May 01.
DOI: 10.1038/s41586-024-07326-y
Abstrakt: 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 remains unknown 1-3 . The major facilitator superfamily transporter FLVCR1 (also known as MFSD7B or SLC49A1) was recently determined to be a choline transporter but is not highly expressed at the blood-brain barrier, whereas the related protein FLVCR2 (also known as MFSD7C or SLC49A2) is expressed in endothelial cells at the blood-brain barrier 4-7 . 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 4,5 . 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 both inward-facing and outward-facing states using cryo-electron microscopy. 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 therapeutic agents into the brain.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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