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

doi:10.1038/s41586-024-07326-y

. 2024 May;629(8012):704-709.

doi: 10.1038/s41586-024-07326-y. Epub 2024 May 1.

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

Rosemary J Cater^#^{1

2}, Dibyanti Mukherjee^#³, Eva Gil-Iturbe⁴, Satchal K Erramilli⁵, Ting Chen⁶, Katie Koo³, Nicolás Santander⁷, Andrew Reckers⁸, Brian Kloss⁶, Tomasz Gawda⁵, Brendon C Choy⁶, Zhening Zhang⁹, Aditya Katewa³, Amara Larpthaveesarp³, Eric J Huang^{10

11}, Scott W J Mooney¹², Oliver B Clarke^{6

13}, Sook Wah Yee¹⁴, Kathleen M Giacomini¹⁴, Anthony A Kossiakoff⁵, Matthias Quick^{6

4

15}, Thomas Arnold¹⁶, Filippo Mancia¹⁷

Affiliations

¹ Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. r.cater@uq.edu.au.
² Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia. r.cater@uq.edu.au.
³ Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
⁶ Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
⁷ Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile.
⁸ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
⁹ Cryo-Electron Microscopy Center, Columbia University, New York, NY, USA.
¹⁰ Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Pathology Service, San Francisco VA Medical Center, San Francisco, CA, USA.
¹² Burke Neurological Institute, White Plains, NY, USA.
¹³ Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
¹⁴ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
¹⁵ New York State Psychiatric Institute, Area Neuroscience-Molecular Therapeutics, New York, NY, USA.
¹⁶ Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA. thomas.arnold@ucsf.edu.
¹⁷ Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. fm123@cumc.columbia.edu.

^# Contributed equally.

PMID: 38693257
PMCID: PMC11168207 (available on 2025-05-01)
DOI: 10.1038/s41586-024-07326-y

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

Rosemary J Cater et al. Nature. 2024 May.

. 2024 May;629(8012):704-709.

doi: 10.1038/s41586-024-07326-y. Epub 2024 May 1.

Authors

Affiliations

¹ Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. r.cater@uq.edu.au.
² Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia. r.cater@uq.edu.au.
³ Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
⁶ Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
⁷ Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile.
⁸ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
⁹ Cryo-Electron Microscopy Center, Columbia University, New York, NY, USA.
¹⁰ Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Pathology Service, San Francisco VA Medical Center, San Francisco, CA, USA.
¹² Burke Neurological Institute, White Plains, NY, USA.
¹³ Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
¹⁴ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
¹⁵ New York State Psychiatric Institute, Area Neuroscience-Molecular Therapeutics, New York, NY, USA.
¹⁶ Department of Pediatrics, Neonatal Brain Research Institute, University of California San Francisco, San Francisco, CA, USA. thomas.arnold@ucsf.edu.
¹⁷ Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. fm123@cumc.columbia.edu.

^# Contributed equally.

PMID: 38693257
PMCID: PMC11168207 (available on 2025-05-01)
DOI: 10.1038/s41586-024-07326-y

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 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.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Update of

Structural and molecular basis of choline uptake into the brain by FLVCR2.
Cater RJ, Mukherjee D, Iturbe EG, Erramilli SK, Chen T, Koo K, Grez NS, Reckers A, Kloss B, Gawda T, Choy BC, Zheng Z, Clarke OB, Yee SW, Kossiakoff AA, Quick M, Arnold T, Mancia F. Cater RJ, et al. bioRxiv [Preprint]. 2023 Oct 5:2023.10.05.561059. doi: 10.1101/2023.10.05.561059. bioRxiv. 2023. Update in: Nature. 2024 May;629(8012):704-709. doi: 10.1038/s41586-024-07326-y PMID: 37873173 Free PMC article. Updated. Preprint.

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Che J, Sun Y, Deng Y, Zhang J. Che J, et al. Fluids Barriers CNS. 2024 Aug 7;21(1):63. doi: 10.1186/s12987-024-00563-3. Fluids Barriers CNS. 2024. PMID: 39113115 Free PMC article. Review.
Proteomic Profiling Reveals Age-Related Changes in Transporter Proteins in the Human Blood-Brain Barrier.
Zhou X, Azimi M, Handin N, Riselli A, Vora B, Chun E, Yee SW, Artursson P, Giacomini KM. Zhou X, et al. bioRxiv [Preprint]. 2024 Jul 27:2024.07.26.604313. doi: 10.1101/2024.07.26.604313. bioRxiv. 2024. PMID: 39091855 Free PMC article. Preprint.

References

1. Zeisel SH & da Costa K-A Choline: an essential nutrient for public health. Nutrition Reviews 67, 615–623 (2009). - PMC - PubMed
1. Zeisel SH Choline: Critical Role During Fetal Development and Dietary Requirements in Adults. Annu Rev Nutr 26, 229–250 (2006). - PMC - PubMed
1. 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), Washington (DC), 1998). - PubMed
1. Hupe M et al. Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels. Science Signaling 10, eaag2476 (2017). - PubMed
1. Santander N et al. Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier. J Clin Invest 130, 4055–4068 (2020). - PMC - PubMed

Additional References

1. Li Y et al. MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme. Nat Commun 11, 4837 (2020). - PMC - PubMed
1. Sabbagh MF & Nathans J A genome-wide view of the de-differentiation of central nervous system endothelial cells in culture. Elife 9, e51276 (2020). - PMC - PubMed
1. Semesta KM, Garces A & Tsvetanova NG The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction. J Biol Chem 299, 105133 (2023). - PMC - PubMed
1. Assur Z, Hendrickson WA & Mancia F Tools for coproducing multiple proteins in mammalian cells. Methods Mol Biol 801, 173–87 (2012). - PMC - PubMed
1. Kawate T & Gouaux E Fluorescence-detection size-exclusion chromatography for precrystallization screening of integral membrane proteins. Structure 14, 673–81 (2006). - PubMed

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[1] Zeisel SH & da Costa K-A Choline: an essential nutrient for public health. Nutrition Reviews 67, 615–623 (2009). - PMC - PubMed

[2] Zeisel SH & da Costa K-A Choline: an essential nutrient for public health. Nutrition Reviews 67, 615–623 (2009). - PMC - PubMed

[3] Zeisel SH Choline: Critical Role During Fetal Development and Dietary Requirements in Adults. Annu Rev Nutr 26, 229–250 (2006). - PMC - PubMed

[4] Zeisel SH Choline: Critical Role During Fetal Development and Dietary Requirements in Adults. Annu Rev Nutr 26, 229–250 (2006). - PMC - PubMed

[5] 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), Washington (DC), 1998). - PubMed

[6] 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), Washington (DC), 1998). - PubMed

[7] Hupe M et al. Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels. Science Signaling 10, eaag2476 (2017). - PubMed

[8] Hupe M et al. Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels. Science Signaling 10, eaag2476 (2017). - PubMed

[9] Santander N et al. Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier. J Clin Invest 130, 4055–4068 (2020). - PMC - PubMed

[10] Santander N et al. Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier. J Clin Invest 130, 4055–4068 (2020). - PMC - PubMed

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

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

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