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

Rosemary J. Cater (), Dibyanti Mukherjee, Eva Gil-Iturbe, Satchal K. Erramilli, Ting Chen, Katie Koo, Nicolás Santander, Andrew Reckers, Brian Kloss, Tomasz Gawda, Brendon C. Choy, Zhening Zhang, Aditya Katewa, Amara Larpthaveesarp, Eric J. Huang, Scott W. J. Mooney, Oliver B. Clarke, Sook Wah Yee, Kathleen M. Giacomini, Anthony A. Kossiakoff, Matthias Quick, Thomas Arnold () and Filippo Mancia ()
Additional contact information
Rosemary J. Cater: Columbia University
Dibyanti Mukherjee: Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco
Eva Gil-Iturbe: Columbia University Irving Medical Center
Satchal K. Erramilli: University of Chicago
Ting Chen: Columbia University
Katie Koo: Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco
Nicolás Santander: Universidad de O’Higgins
Andrew Reckers: Columbia University
Brian Kloss: Columbia University
Tomasz Gawda: University of Chicago
Brendon C. Choy: Columbia University
Zhening Zhang: Columbia University
Aditya Katewa: Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco
Amara Larpthaveesarp: Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco
Eric J. Huang: San Francisco
Scott W. J. Mooney: Burke Neurological Institute
Oliver B. Clarke: Columbia University
Sook Wah Yee: University of California
Kathleen M. Giacomini: University of California
Anthony A. Kossiakoff: University of Chicago
Matthias Quick: Columbia University
Thomas Arnold: Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco
Filippo Mancia: Columbia University

Nature, 2024, vol. 629, issue 8012, 704-709

Abstract: 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 remains unknown1–3. 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 barrier4–7. Previous studies have shown that mutations in human Flvcr2 cause cerebral vascular abnormalities, hydrocephalus and embryonic lethality, but the physiological role of FLVCR2 is unknown4,5. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07326-y

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