Structure and transport mechanism of human riboflavin transporters
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.
Authors
- Daohua Jiang (ORCID: https://orcid.org/0000-0002-4397-5807)
- Xin He (ORCID: https://orcid.org/0000-0002-5618-1774)
- Huiwen Chen (ORCID: https://orcid.org/0000-0001-5269-2334)
- Feng Zhou (ORCID: https://orcid.org/0000-0001-9040-1796)
- Lili Cheng (ORCID: https://orcid.org/0000-0001-8009-1069)
- Juquan Jiang (ORCID: https://orcid.org/0000-0001-8121-4518)
- Jun Zhao (ORCID: https://orcid.org/0009-0006-6190-0469)
- Yumeng Zhou (ORCID: https://orcid.org/0009-0003-3268-884X)
- Ligong Chen (ORCID: https://orcid.org/0000-0002-7893-7173)
- Bo Huang (ORCID: https://orcid.org/0000-0003-3822-9110)
- Di Wu (ORCID: https://orcid.org/0000-0003-2271-4963)
- Ke Wang (ORCID: https://orcid.org/0000-0001-7058-7853)
- Y. Yuan (ORCID: https://orcid.org/0000-0001-6698-9497)
Institutions
- Northeast Agricultural University (CN)
- Chinese Academy of Sciences (CN)
- FZU ‒ Institute of Physics of the Academy of Sciences of the Czech Republic (CZ)
- Institute of Physics (CN)
- National Laboratory for Superconductivity (CN)
- University of Chinese Academy of Sciences (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1038/s41467-025-59255-7
- Citations
- 6
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 7.91
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Peking University
- Beijing Municipal Science and Technology Commission