Structural basis for saxitoxin congener binding and neutralization by anuran saxiphilins

Abstract

Abstract Dinoflagellates and cyanobacteria produce saxitoxin (STX) and ~50 congeners that disrupt bioelectrical signals by blocking voltage-gated sodium channels (Na V s). Consuming seafood carrying these toxins causes paralytic shellfish poisoning (PSP). Although Na V 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 ) Rc Sxph and High Himalaya frog ( Nanorana parkeri ) Np Sxph sequester STX congeners using a ‘lock and key’ mode shared with STX. Importantly, functional studies demonstrate that Sxph ‘toxin sponges’ reverse Na V 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 V 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.