TY  - JOUR
A1  - Ri, Keiken
A1  - Weng, Tsai-Hsuan
A1  - Claveras Cabezudo, Ainara
A1  - Jösting, Wiebke
A1  - Zhang, Yu
A1  - Bazzone, Andre
A1  - Leong, Nancy C. P.
A1  - Welsch, Sonja
A1  - Doty, Raymond T.
A1  - Gursu, Gonca
A1  - Lim, Tiffany Jia Ying
A1  - Schmidt, Sarah Luise
A1  - Abkowitz, Janis L.
A1  - Hummer, Gerhard
A1  - Wu, Di
A1  - Nguyen, Long N.
A1  - Safarian, Schara
T1  - Molecular mechanism of choline and ethanolamine transport in humans
T2  - Nature
N2  - 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 syndrome2,3,4,5,6,7. Earlier studies concluded that FLVCR1 may function as a haem exporter8,9,10,11,12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14,15,16. 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.
KW  - Computational models
KW  - Cryoelectron microscopy
KW  - Membrane proteins
Y1  - 2024
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/85731
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-857314
SN  - 1476-4687
VL  - 2024
PB  - Macmillan Publishers Limited, part of Springer Nature  London : Macmillan [anfangs]
CY  - London
ER  -