Structure and transport mechanism of human riboflavin transporters

Ke Wang, Huiwen Chen, Lili Cheng, Jun Zhao, Bo Huang, Di Wu, Xin He, Yumeng Zhou, Yaxuan Yuan, Feng Zhou, Juquan Jiang (), Ligong Chen () and Daohua Jiang ()
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Ke Wang: Northeast Agricultural University
Huiwen Chen: Northeast Agricultural University
Lili Cheng: Tsinghua University
Jun Zhao: Shandong Laboratory of Advanced Agricultural Sciences at Weifang
Bo Huang: Beijing StoneWise Technology Co Ltd.
Di Wu: Chinese Academy of Sciences
Xin He: Tsinghua University
Yumeng Zhou: Tsinghua University
Yaxuan Yuan: Tsinghua University
Feng Zhou: Beijing StoneWise Technology Co Ltd.
Juquan Jiang: Northeast Agricultural University
Ligong Chen: Tsinghua University
Daohua Jiang: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Riboflavin (vitamin B2) is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which act as key cofactors of many enzymes, thus has essential roles in cell growth and functions. Animals cannot synthesize riboflavin in situ, the intake, distribution and metabolism of which are mediated by three riboflavin transporters (RFVT1-3). Many mutations in RFVTs cause severe consequences. How RFVTs recognize and transport riboflavin remains largely unknown. Here we describe the cryo-electron microscopy structures of human RFVT2 and RFVT3 in complex with riboflavin in outward-occluded and inward-open states, respectively. Riboflavin is recognized by a conserved binding pocket in the central cavity of RFVTs, whereas two acidic residues in RFVT3 determine its pH-dependent activity. By combining the structural, computational and functional analyses, this study demonstrates the structural basis of riboflavin recognition and provides a structural framework for the mechanistic comprehension of riboflavin recognition, transport, and pathology in human RFVTs.

Date: 2025
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DOI: 10.1038/s41467-025-59255-7

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