德国马克斯·普朗克生物物理研究所Schara Safarian等研究人员合作揭示人类胆碱和乙醇胺转运的分子机制。该研究于2024年5月22日在线发表于国际一流学术期刊《自然》。

研究人员发现猫白血病病毒C亚群受体相关蛋白1和2（FLVCR1和FLVCR2）通过浓度驱动的底物转运过程促进胆碱和乙醇胺跨质膜转运。通过结构和计算分析，研究人员确定了FLVCR不同的构象状态，并揭示了它们与底物相互作用的配位化学原理。完全保守的色氨酸和酪氨酸残基构成了这两种转运体的结合口袋，并通过阳离子-π相互作用赋予胆碱和乙醇胺选择性。这些发现阐明了FLVCR1和FLVCR2转运胆碱和乙醇胺的机制，提高了人们对干扰这些重要过程的疾病相关突变的理解，并阐明了这些主要促进剂超家族蛋白在转运循环过程中的构象动态。

据介绍，人类FLVCR1和FLVCR2是主要促进因子超家族的成员。它们的功能障碍与多种临床疾病有关，包括PCARP、HSAN和Fowler综合征。早先的研究认为，FLVCR1可能具有血红素输出功能，而FLVCR2则被认为具有血红素输入功能，但对于这两种转运体的功能，仍然没有确凿的生化和详细的分子证据。

附：英文原文

Title: Molecular mechanism of choline and ethanolamine transport in humans

Author: Ri, Keiken, Weng, Tsai-Hsuan, Claveras Cabezudo, Ainara, Jsting, Wiebke, Zhang, Yu, Bazzone, Andre, Leong, Nancy C. P., Welsch, Sonja, Doty, Raymond T., Gursu, Gonca, Lim, Tiffany Jia Ying, Schmidt, Sarah Luise, Abkowitz, Janis L., Hummer, Gerhard, Wu, Di, Nguyen, Long N., Safarian, Schara

Issue&Volume: 2024-05-22

Abstract: 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.

DOI: 10.1038/s41586-024-07444-7

Source: https://www.nature.com/articles/s41586-024-07444-7