Zakrzewska Sandra, Nixon Samantha A, Chen Zhou, Hajare Holly S, Park Elizabeth R, Mulcahy John V, Arlinghaus Kandis M, Neu Eduard, Konovalov Kirill, Provasi Davide, Leighfield Tod A, Filizola Marta, Du Bois J, Minor Daniel L
Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Commun. 2025 Apr 24;16(1):3885. doi: 10.1038/s41467-025-58903-2.
Dinoflagellates and cyanobacteria produce saxitoxin (STX) and ~50 congeners that disrupt bioelectrical signals by blocking voltage-gated sodium channels (Nas). Consuming seafood carrying these toxins causes paralytic shellfish poisoning (PSP). Although Nas 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 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 Nas. These findings expand understanding of toxin sponge action and provide a foundation for strategies to monitor and mitigate the harmful effects of STX congeners.
甲藻和蓝细菌会产生石房蛤毒素（STX）及其约50种同类物，这些物质通过阻断电压门控钠通道（Na通道）来干扰生物电信号。食用携带这些毒素的海鲜会导致麻痹性贝类中毒（PSP）。尽管Na通道和无尾类动物的STX结合蛋白（石房蛤毒素结合蛋白，Sxphs）采用趋同的STX结合模式，但STX同类物识别的结构基础尚不清楚。在此，我们表明美国牛蛙（Rana catesbeiana）的RcSxph和喜马拉雅高山蛙（Nanorana parkeri）的NpSxph使用与STX共享的“锁钥”模式来螯合STX同类物。重要的是，功能研究表明，Sxph“毒素海绵”可逆转多种STX同类物对Na通道的阻断，并在用于环境检测的放射性配体结合分析（RBA）中检测到这些毒素。总之，我们的研究确定了Sxphs如何螯合特定的神经毒素，并揭示了与Na通道不同的STX同类物特异性相互作用。这些发现扩展了对毒素海绵作用的理解，并为监测和减轻STX同类物有害影响的策略奠定了基础。
