TY  - INPR
A1  - Weng, Tsai-Hsuan
A1  - Claveras Cabezudo, Ainara
A1  - Jösting, Wiebke
A1  - Bazzone, Andre
A1  - Welsch, Sonja
A1  - Gursu, Gonca
A1  - Hummer, Gerhard
A1  - Wu, Di
A1  - Safarian, Schara
T1  - Structural and mechanistic insights into human choline transport
T2  - bioRxiv
N2  - 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.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/79448
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-794488
UR  - https://www.biorxiv.org/content/10.1101/2023.09.15.557925v1
IS  - 2023.09.15.557925 Version 1
ER  -