Structural and mechanistic insights into human choline and ethanolamine transport

  • Human feline leukemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and 2) 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 putative heme exporter8–12, while FLVCR2 was suggested to act as a heme importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14–17. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across human plasma membranes, utilizing a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unraveled the coordination chemistry underlying their substrate interactions. Within the binding pocket of both transporters, we identify fully conserved tryptophan and tyrosine residues holding a central role in the formation of cation-π interactions, essential for choline and ethanolamine selectivity. Our findings not only clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhancing our comprehension of disease-associated mutations that interfere with these vital processes, but also shed light on the conformational dynamics of these MFS-type proteins during the transport cycle.

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Author:Keiken RiORCiD, Tsai-Hsuan WengORCiDGND, Ainara Claveras CabezudoORCiDGND, Wiebke JöstingORCiD, Zhang Yu, Andre BazzoneORCiDGND, Nancy C. P. LeongORCiD, Sonja WelschORCiDGND, Raymond T. DotyORCiD, Gonca GursuORCiD, Tiffany Jia Ying Lim, Luise Sarah Schmidt, Janis L. Abkowitz, Gerhard HummerORCiD, Di WuORCiDGND, Long N. NguyenORCiD, Schara SafarianORCiDGND
URN:urn:nbn:de:hebis:30:3-830264
URL:https://www.biorxiv.org/content/10.1101/2023.09.15.557925v2
DOI:https://doi.org/10.1101/2023.09.15.557925
Parent Title (English):bioRxiv
Publisher:bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2023/12/19
Date of first Publication:2023/12/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/06/04
Issue:2023.09.15.557925 Version 2
Edition:Version 2
Page Number:48
HeBIS-PPN:519853393
Institutes:Physik / Physik
Angeschlossene und kooperierende Institutionen / MPI für Biophysik
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International