Do not poison thyself

Hunter, Philip

doi:10.15252/embr.201846756

Cited by 3 publications

(3 citation statements)

References 8 publications

(11 reference statements)

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“…Organisms are thought to cope with toxin exposure through diverse strategies that include target protein resistance mutations, toxin sequestration, and toxin removal ( 10 , 11 ). Frogs are resistant to STX ( 14 , 15 ), and Sxph may contribute to this property ( 16 , 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…Nature uses diverse strategies to counter toxin exposure that include target protein resistance mutations, toxin sequestration, and toxin removal ( 10 , 11 ). Although the best understood toxin resistance strategies involve target protein mutations ( 10 , 12 , 13 ), frogs display unusual resistance to STX poisoning ( 14 , 15 ) that is not believed to involve altered responses of frog Na V s to STX ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins

et al. 2019

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Dinoflagelates and cyanobacteria produce saxitoxin (STX), a lethal bis-guanidinium neurotoxin causing paralytic shellfish poisoning. A number of metazoans have soluble STX-binding proteins that may prevent STX intoxication. However, their STX molecular recognition mechanisms remain unknown. Here, we present structures of saxiphilin (Sxph), a bullfrog high-affinity STX-binding protein, alone and bound to STX. The structures reveal a novel high-affinity STX-binding site built from a “proto-pocket” on a transferrin scaffold that also bears thyroglobulin domain protease inhibitor repeats. Comparison of Sxph and voltage-gated sodium channel STX-binding sites reveals a convergent toxin recognition strategy comprising a largely rigid binding site where acidic side chains and a cation-π interaction engage STX. These studies reveal molecular rules for STX recognition, outline how a toxin-binding site can be built on a naïve scaffold, and open a path to developing protein sensors for environmental STX monitoring and new biologics for STX intoxication mitigation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins

et al. 2019

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“…This lipophilic, steroidal neurotoxin is thought to bind in the Na V inner pore ( Wang and Wang, 2003 ). How vertebrates that bear BTX or other small-molecule toxins avoid autointoxication remains unresolved ( Arbuckle et al, 2017 ; Almabruk et al, 2018 ; Hunter, 2018 ). Toxin-resistant mutants of target ion channels in host organisms ( Tarvin et al, 2017 ; Bricelj et al, 2005 ; Hanifin and Gilly, 2015 ; Jost et al, 2008 ) or their predators ( Geffeney et al, 2002 ; Geffeney et al, 2005 ; McGlothlin et al, 2016 ) have been suggested as the primary drivers of toxin resistance ( Santos et al, 2016 ), an idea supported by examples of tetrodotoxin (TTX)-resistant ( Hanifin and Gilly, 2015 ; Jost et al, 2008 ; Geffeney et al, 2002 ; Geffeney et al, 2005 ; McGlothlin et al, 2016 ) and saxitoxin (STX)-resistant ( Bricelj et al, 2005 ) Na V s, as well as epibatidine-resistant nicotinic acetylcholine receptors ( Tarvin et al, 2017 ) found in toxin-carrying metazoans.…”

Section: Introductionmentioning

confidence: 99%

Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on “toxin sponge” proteins

Abderemane-Ali

Rossen

Kobiela

et al. 2021

Journal of General Physiology

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Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog NaVs. We also show that captivity-raised poison frogs are resistant to two NaV-directed toxins, BTX and saxitoxin (STX), even though they bear NaVs sensitive to both. Moreover, we demonstrate that the amphibian STX “toxin sponge” protein saxiphilin is able to protect and rescue NaVs from block by STX. Taken together, our data contradict the hypothesis that BTX autoresistance is rooted in the DIVS6 N→T mutation, challenge the idea that ion channel mutations are a primary driver of toxin resistance, and suggest the possibility that toxin sequestration mechanisms may be key for protecting poisonous species from the action of small-molecule toxins.

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Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs

Abderemane-Ali¹,

Rossen²,

Kobiela

et al. 2020

Preprint

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Poisonous organisms carry small molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui toxic birds and Phyllobates poison frogs, stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore forming helix N->T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost that compromises channel function, and fails to produce BTX resistant channels when tested in the context of poison frog NaVs. We further show that captive-raised poison frogs are BTX resistant, even though they bear BTX sensitive NaVs. Hence, our data refute the hypothesis that BTX autoresistance is rooted in NaV mutations and instead suggest that more generalizable mechanisms such as toxin sequestration act to protect BTX bearing species from autointoxication.

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Do not poison thyself

Abstract: The mechanisms by which poisonous plants and animals protect themselves against their own toxins provide interesting leads for synthetic biology with potential applications in medicine and agriculture.

Cited by 3 publications

References 8 publications

Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins

Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins

Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on “toxin sponge” proteins

Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs

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