Molecular mechanism of choline and ethanolamine transport in humans

Keiken Ri, Tsai-Hsuan Weng, Ainara Claveras Cabezudo, Wiebke Jösting, Yu Zhang, Andre Bazzone, Nancy C. P. Leong, Sonja Welsch, Raymond T. Doty, Gonca Gursu, Tiffany Jia Ying Lim, Sarah Luise Schmidt, Janis L. Abkowitz, Gerhard Hummer (), Di Wu (), Long N. Nguyen () and Schara Safarian ()
Additional contact information
Keiken Ri: National University of Singapore
Tsai-Hsuan Weng: Max Planck Institute of Biophysics
Ainara Claveras Cabezudo: Max Planck Institute of Biophysics
Wiebke Jösting: Max Planck Institute of Biophysics
Yu Zhang: National University of Singapore
Andre Bazzone: Nanion Technologies GmbH
Nancy C. P. Leong: National University of Singapore
Sonja Welsch: Max Planck Institute of Biophysics
Raymond T. Doty: University of Washington
Gonca Gursu: Max Planck Institute of Biophysics
Tiffany Jia Ying Lim: National University of Singapore
Sarah Luise Schmidt: Max Planck Institute of Biophysics
Janis L. Abkowitz: University of Washington
Gerhard Hummer: Max Planck Institute of Biophysics
Di Wu: Max Planck Institute of Biophysics
Long N. Nguyen: National University of Singapore
Schara Safarian: Max Planck Institute of Biophysics

Nature, 2024, vol. 630, issue 8016, 501-508

Abstract: 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 syndrome2–7. Earlier studies concluded that FLVCR1 may function as a haem exporter8–12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14–16. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07444-7

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