Structural and mechanistic insights into human choline transport

  • Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and 2) are major facilitator superfamily transporters from the solute carrier family 49. Dysregulation of these ubiquitous transporters has been linked to various haematological and neurological disorders. While both FLVCRs were initially proposed to hold a physiological function in heme transport, subsequent studies questioned this notion. Here, we used structural, computational and biochemical methods and conclude that these two FLVCRs function as human choline transporters. We present cryo-electron microscopy structures of FLVCRs in different inward- and outward-facing conformations, captured in the apo state or in complex with choline in their translocation pathways. Our findings provide insights into the molecular framework of choline coordination and transport, largely mediated by conserved cation-π interactions, and further illuminate the conformational dynamics of the transport cycle. Moreover, we identified a heme binding site on the protein surface of the FLVCR2 N-domain, and observed that heme actively drives the conformational transitions of the protein. This auxiliary binding site might indicate a potential regulatory role of heme in the FLVCR2 transport mechanisms. Our work resolves the contested substrate specificity of the FLVCRs, and sheds light on the process of maintaining cellular choline homeostasis at the molecular level.

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Author:Tsai-Hsuan WengORCiDGND, Ainara Claveras CabezudoORCiDGND, Wiebke JöstingORCiD, Andre BazzoneORCiDGND, Sonja WelschORCiDGND, Gonca Gursu, Gerhard HummerORCiD, Di WuORCiDGND, Schara SafarianORCiDGND
Parent Title (English):bioRxiv
Document Type:Preprint
Date of Publication (online):2023/09/15
Date of first Publication:2023/09/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/11/06
Issue:2023.09.15.557925 Version 1
Edition:Version 1
Page Number:52
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
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International