Structural basis for saxitoxin congener binding and neutralization by anuran saxiphilins
Dinoflagellates and cyanobacteria produce saxitoxin (STX) and ~50 congeners that disrupt bioelectrical signals by blocking voltage-gated sodium channels (Na<sub>V</sub>s). Consuming seafood carrying these toxins causes paralytic shellfish poisoning (PSP). Although Na<sub>V</sub>s and anuran STX binding proteins (saxiphilins, Sxphs) use convergent STX binding modes, the structural basis for STX congener recognition is unknown. Here, we show that American bullfrog (Rana catesbeiana) RcSxph and High Himalaya frog (Nanorana parkeri) NpSxph sequester STX congeners using a 'lock and key' mode shared with STX. Importantly, functional studies demonstrate that Sxph 'toxin sponges' reverse Na<sub>V</sub> block by multiple STX congeners and detect these toxins in a radioligand binding assay (RBA) used for environmental testing. Together, our study establishes how Sxphs sequester select neurotoxins and uncover STX congener-specific interactions distinct from Na<sub>V</sub>s. These findings expand understanding of toxin sponge action and provide a foundation for strategies to monitor and mitigate the harmful effects of STX congeners.
Authors
- Marta Filizola (ORCID: https://orcid.org/0000-0002-4382-8276)
- J. Du Bois (ORCID: https://orcid.org/0000-0001-7847-1548)
- Samantha A. Nixon (ORCID: https://orcid.org/0000-0003-3157-4114)
- Tod A. Leighfield (ORCID: https://orcid.org/0000-0002-6780-8800)
- Daniel L. Minor (ORCID: https://orcid.org/0000-0002-5998-4214)
- Kirill A. Konovalov
- John V. Mulcahy (ORCID: https://orcid.org/0000-0002-3997-6073)
- Sandra Zakrzewska (ORCID: https://orcid.org/0000-0002-8706-4394)
- Eduard Neu (ORCID: https://orcid.org/0000-0003-2999-1488)
- Elizabeth R. Park (ORCID: https://orcid.org/0000-0001-9974-3899)
- Zhou Chen (ORCID: https://orcid.org/0000-0002-4426-2497)
- Kandis M Arlinghaus (ORCID: https://orcid.org/0000-0002-9020-1935)
- Holly S. Hajare (ORCID: https://orcid.org/0009-0002-2682-4940)
- Davide Provasi
Institutions
- QB3 (US)
- National Oceanic and Atmospheric Administration (US)
- Lawrence Berkeley National Laboratory (US)
- University of California, San Francisco (US)
- Shanghai Jiao Tong University (CN)
- National Institute of Fundamental Studies (LK)
- Quantitative BioSciences (US)
- NOAA National Centers for Coastal Ocean Science (US)
- Stanford University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1038/s41467-025-58903-2
- Citations
- 4
- Primary Topic
- Marine Toxins and Detection Methods
- Type
- article
- Field-Weighted Citation Impact
- 3.44
Funders
- U.S. Department of Energy
- Georgia Clinical and Translational Science Alliance
- Studienstiftung des Deutschen Volkes
- National Institutes of Health
- National Oceanic and Atmospheric Administration
- Defense Threat Reduction Agency
- Oak Ridge Institute for Science and Education
- National Institute of General Medical Sciences
- National Center for Advancing Translational Sciences
- NOAA Research