Structural basis for saxitoxin congener binding and neutralization by anuran saxiphilins

Sandra Zakrzewska, Samantha A. Nixon, Zhou Chen, Holly S. Hajare, Elizabeth R. Park, John V. Mulcahy, Kandis M. Arlinghaus, Eduard Neu, Kirill Konovalov, Davide Provasi, Tod A. Leighfield, Marta Filizola, J. Bois and Daniel L. Minor ()
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Sandra Zakrzewska: University of California
Samantha A. Nixon: University of California
Zhou Chen: University of California
Holly S. Hajare: Stanford University
Elizabeth R. Park: Stanford University
John V. Mulcahy: Stanford University
Kandis M. Arlinghaus: National Centers for Coastal Ocean Science
Eduard Neu: Ichan School of Medicine at Mount Sinai
Kirill Konovalov: Ichan School of Medicine at Mount Sinai
Davide Provasi: Ichan School of Medicine at Mount Sinai
Tod A. Leighfield: National Centers for Coastal Ocean Science
Marta Filizola: Ichan School of Medicine at Mount Sinai
J. Bois: Stanford University
Daniel L. Minor: University of California

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

Abstract: Abstract Dinoflagellates and cyanobacteria produce saxitoxin (STX) and ~50 congeners that disrupt bioelectrical signals by blocking voltage-gated sodium channels (NaVs). Consuming seafood carrying these toxins causes paralytic shellfish poisoning (PSP). Although NaVs 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 NaV 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 NaVs. These findings expand understanding of toxin sponge action and provide a foundation for strategies to monitor and mitigate the harmful effects of STX congeners.

Date: 2025
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DOI: 10.1038/s41467-025-58903-2

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