TY  - INPR
A1  - Ri, Keiken
A1  - Weng, Tsai-Hsuan
A1  - Claveras Cabezudo, Ainara
A1  - Jösting, Wiebke
A1  - Yu, Zhang
A1  - Bazzone, Andre
A1  - Leong, Nancy C. P.
A1  - Welsch, Sonja
A1  - Doty, Raymond T.
A1  - Gursu, Gonca
A1  - Lim, Tiffany Jia Ying
A1  - Luise Schmidt, Sarah
A1  - Abkowitz, Janis L.
A1  - Hummer, Gerhard
A1  - Wu, Di
A1  - Nguyen, Long N.
A1  - Safarian, Schara
T1  - Structural and mechanistic insights into human choline and ethanolamine transport
T2  - bioRxiv
N2  - 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.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/83026
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-830264
UR  - https://www.biorxiv.org/content/10.1101/2023.09.15.557925v2
IS  - 2023.09.15.557925 Version 2
PB  - bioRxiv
ER  -