Molecular mechanism of choline and ethanolamine transport in humans

Ri, Keiken; Weng, Tsai-Hsuan; Claveras Cabezudo, Ainara; Jösting, Wiebke; Zhang, Yu; Bazzone, Andre; Leong, Nancy C. P.; Welsch, Sonja; Doty, Raymond T.; Gursu, Gonca; Lim, Tiffany Jia Ying; Schmidt, Sarah Luise; Abkowitz, Janis L.; Hummer, Gerhard; Wu, Di; Nguyen, Long N.; Safarian, Schara

doi:10.1038/s41586-024-07444-7

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Molecular mechanism of choline and ethanolamine transport in humans

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Weng, Tsai-Hsuan
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Claveras Cabezudo, Ainara
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;
IMPRS-CBP, Max Planck Institute of Biophysics, Max Planck Society;

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Jösting, Wiebke
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Welsch, Sonja
Central Electron Microscopy Facility, Max Planck Institute of Biophysics, Max Planck Society;

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Gursu, Gonca
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Schmidt, Sarah Luise
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Hummer, Gerhard
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;
Institute of Biophysics, Goethe University Frankfurt, Frankfurt, Germany;

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Wu, Di
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Safarian, Schara
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, Germany;
Institute of Clinical Pharmacology, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany;
Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Frankfurt, Germany;

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Citation

Ri, K., Weng, T.-H., Claveras Cabezudo, A., Jösting, W., Zhang, Y., Bazzone, A., et al. (2024). Molecular mechanism of choline and ethanolamine transport in humans. Nature. doi:10.1038/s41586-024-07444-7.

Cite as: https://hdl.handle.net/21.11116/0000-000F-5067-3

Abstract

Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily¹. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome^2-7. Earlier studies concluded that FLVCR1 may function as a haem exporter^8-12, whereas FLVCR2 was suggested to act as a haem importer¹³, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters^14-16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.