Conserved hydrophilic checkpoints tune FocA-mediated formate:H+ symport
FocA belongs to the widespread, evolutionarily ancient formate-nitrite transporter (FNT) family of pentameric anion channels and translocates formic acid bidirectionally. Here, we identify compartmentalized polarity distribution across the complete FocA pore structure - resolved at 2.56 Å - mirrored against a two-fold axis with H209 at its center. A FocA-H209N variant that exhibits an efflux-only channel-like function in vivo reveals a density consistent with formate located directly at N209, abolishing the channel's amphiphilicity. Pyruvate formate-lyase, which generates formate, orients at the cytoplasmic face where formate delivery is regulated by conformational changes in the FocA vestibule. Comparisons with other FNTs suggest a tuning mechanism of formate-specific transport via checkpoints enriched in hydrophilic residues.
Authors
- Fotis L. Kyrilis (ORCID: https://orcid.org/0000-0002-4040-6289)
- Panagiotis L. Kastritis (ORCID: https://orcid.org/0000-0002-1463-8422)
- Michelle Kammel (ORCID: https://orcid.org/0000-0002-8082-9796)
- Farzad Hamdi (ORCID: https://orcid.org/0000-0002-2155-5000)
- C Tueting (ORCID: https://orcid.org/0000-0001-6209-4012)
- R. Gary Sawers (ORCID: https://orcid.org/0000-0003-0862-2683)
- Christopher Erdmann (ORCID: https://orcid.org/0000-0003-2554-180X)
- K Janson (ORCID: https://orcid.org/0000-0002-8621-6130)
- Christian Ihling (ORCID: https://orcid.org/0000-0003-2419-4391)
- Andrea Sinz (ORCID: https://orcid.org/0000-0003-1521-4899)
- Jana Lorenz
Institutions
- National Hellenic Research Foundation (GR)
- Martin Luther University Halle-Wittenberg (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1038/s41467-025-65159-3
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Bundesministerium für Wirtschaft und Energie
- HORIZON EUROPE Framework Programme
- European Regional Development Fund