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

• Published in: Nature (London) Vol. 629; no. 8012; pp. 704 - 709
• Main Authors: Cater, Rosemary J, Mukherjee, Dibyanti, Gil-Iturbe, Eva, Erramilli, Satchal K, Chen, Ting, Koo, Katie, Santander, Nicolás, Reckers, Andrew, Kloss, Brian, Gawda, Tomasz, Choy, Brendon C, Zhang, Zhening, Katewa, Aditya, Larpthaveesarp, Amara, Huang, Eric J, Mooney, Scott W J, Clarke, Oliver B, Yee, Sook Wah, Giacomini, Kathleen M, Kossiakoff, Anthony A, Quick, Matthias, Arnold, Thomas, Mancia, Filippo
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2024
• Subjects: Abnormalities; Angiogenesis; Animals; Biological Transport; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain; Brain - metabolism; Cell membranes; Choline; Choline - metabolism; CRISPR; Cryoelectron Microscopy; Electron microscopy; Endothelial cells; Epigenetics; Female; Humans; Hydrocephalus; Lethality; Localization; Male; Membrane Transport Proteins - chemistry; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Metabolism; Metabolites; Mice; Microscopy; Models, Molecular; Mutation; Neurotransmission; Pharmacology; Physiology; Plasma; Proteins; Protons
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07326-y

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 . 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 . 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 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.