Structural Insight into Specificity of Interactions between Nonconventional Three-finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors

Lyukmanova, Ekaterina N.; Шенкарев, Захар О.; Shulepko, Mikhail A.; Paramonov, Alexander S.; Chugunov, Anton O.; Janickova, Helena; Dolejší, Eva; Doležal, Vladimı́r; Utkin, Yuri N.; Tsetlin, Victor I.; Arseniev, Alexander S.; Efremov, Roman G.; Долгих, Д. А.; Kirpichnikov, Mikhaǐl P.

doi:10.1074/jbc.m115.656595

Cited by 39 publications

(46 citation statements)

References 46 publications

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“…Potent α-neurotoxicity preceded the evolution of the high-pressure front-fanged system of elapids, as was revealed by our discovery of α-colubritoxin, the first 3FTx isolated and characterized from a non-front-fanged lineage [59]. The toxin was of the same form as had been studied in elapid snakes previously, where they had been called ‘weak neurotoxins’ since they were only weakly potent on mice [137,138,139,140,141,142,143,144,145,146,147,148,149]. A problem that had also confounded studies of Boiga irregularis (brown tree snake), which had thus concluded they were non-venomous based on their effects in a murine model [150,151,152,153,154,155].…”

Section: Resultsmentioning

confidence: 99%

The Snake with the Scorpion’s Sting: Novel Three-Finger Toxin Sodium Channel Activators from the Venom of the Long-Glanded Blue Coral Snake (Calliophis bivirgatus)

Yang

Deuis

Dashevsky

et al. 2016

Toxins

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Millions of years of evolution have fine-tuned the ability of venom peptides to rapidly incapacitate both prey and potential predators. Toxicofera reptiles are characterized by serous-secreting mandibular or maxillary glands with heightened levels of protein expression. These glands are the core anatomical components of the toxicoferan venom system, which exists in myriad points along an evolutionary continuum. Neofunctionalisation of toxins is facilitated by positive selection at functional hotspots on the ancestral protein and venom proteins have undergone dynamic diversification in helodermatid and varanid lizards as well as advanced snakes. A spectacular point on the venom system continuum is the long-glanded blue coral snake (Calliophis bivirgatus), a specialist feeder that preys on fast moving, venomous snakes which have both a high likelihood of prey escape but also represent significant danger to the predator itself. The maxillary venom glands of C. bivirgatus extend one quarter of the snake’s body length and nestle within the rib cavity. Despite the snake’s notoriety its venom has remained largely unstudied. Here we show that the venom uniquely produces spastic paralysis, in contrast to the flaccid paralysis typically produced by neurotoxic snake venoms. The toxin responsible, which we have called calliotoxin (δ-elapitoxin-Cb1a), is a three-finger toxin (3FTx). Calliotoxin shifts the voltage-dependence of NaV1.4 activation to more hyperpolarised potentials, inhibits inactivation, and produces large ramp currents, consistent with its profound effects on contractile force in an isolated skeletal muscle preparation. Voltage-gated sodium channels (NaV) are a particularly attractive pharmacological target as they are involved in almost all physiological processes including action potential generation and conduction. Accordingly, venom peptides that interfere with NaV function provide a key defensive and predatory advantage to a range of invertebrate venomous species including cone snails, scorpions, spiders, and anemones. Enhanced activation or delayed inactivation of sodium channels by toxins is associated with the extremely rapid onset of tetanic/excitatory paralysis in envenomed prey animals. A strong selection pressure exists for the evolution of such toxins where there is a high chance of prey escape. However, despite their prevalence in other venomous species, toxins causing delay of sodium channel inhibition have never previously been described in vertebrate venoms. Here we show that NaV modulators, convergent with those of invertebrates, have evolved in the venom of the long-glanded coral snake. Calliotoxin represents a functionally novel class of 3FTx and a structurally novel class of NaV toxins that will provide significant insights into the pharmacology and physiology of NaV. The toxin represents a remarkable case of functional convergence between invertebrate and vertebrate venom systems in response to similar selection pressures. These results underscore the dynamic evolution of the Toxicofera re...

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Section: Resultsmentioning

confidence: 99%

The Snake with the Scorpion’s Sting: Novel Three-Finger Toxin Sodium Channel Activators from the Venom of the Long-Glanded Blue Coral Snake (Calliophis bivirgatus)

Yang

Deuis

Dashevsky

et al. 2016

Toxins

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“…Conformational exchange processes in SLURP-1, Lypd6, and Lypd6b could be due to cis-trans isomerization of the Xxx-Pro peptide bonds, while in Lynx2 and SLURP-2 the exchange processes can be related to the weak protein oligomerization in solution. Interestingly, wild type WTX demonstrates conformation heterogeneity in solution due to cis-trans isomerization of the Arg32-Pro33 peptide bond located in the loop II; and this dynamic process, similarly to the situation with SLURP-1, influences the loop I conformation [ 43 , 65 ]. WTX-P33A mutant lacks the corresponding Pro residue and, therefore, adopts only one isomeric state in solution.…”

Section: Discussionmentioning

confidence: 99%

Structural Diversity and Dynamics of Human Three-Finger Proteins Acting on Nicotinic Acetylcholine Receptors

Paramonov

Kocharovskaya

Tsarev

et al. 2020

IJMS

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Ly-6/uPAR or three-finger proteins (TFPs) contain a disulfide-stabilized β-structural core and three protruding loops (fingers). In mammals, TFPs have been found in epithelium and the nervous, endocrine, reproductive, and immune systems. Here, using heteronuclear NMR, we determined the three-dimensional (3D) structure and backbone dynamics of the epithelial secreted protein SLURP-1 and soluble domains of GPI-anchored TFPs from the brain (Lynx2, Lypd6, Lypd6b) acting on nicotinic acetylcholine receptors (nAChRs). Results were compared with the data about human TFPs Lynx1 and SLURP-2 and snake α-neurotoxins WTX and NTII. Two different topologies of the β-structure were revealed: one large antiparallel β-sheet in Lypd6 and Lypd6b, and two β-sheets in other proteins. α-Helical segments were found in the loops I/III of Lynx2, Lypd6, and Lypd6b. Differences in the surface distribution of charged and hydrophobic groups indicated significant differences in a mode of TFPs/nAChR interactions. TFPs showed significant conformational plasticity: the loops were highly mobile at picosecond-nanosecond timescale, while the β-structural regions demonstrated microsecond-millisecond motions. SLURP-1 had the largest plasticity and characterized by the unordered loops II/III and cis-trans isomerization of the Tyr39-Pro40 bond. In conclusion, plasticity could be an important feature of TFPs adapting their structures for optimal interaction with the different conformational states of nAChRs.

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“…Similarly, the positively charged residues located at the tip of loop II of toxin WTX, which recognizes the various mAChRs subtypes with low micromolar affinity and limited specificity, were found to be crucial for these interactions (Lyukmanova et al . ).…”

Section: Fts Affecting the Cholinergic Systemmentioning

confidence: 97%

The three‐finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions

Kessler

Marchot

Silva

et al. 2017

Journal of Neurochemistry

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Three-finger fold toxins are miniproteins frequently found in Elapidae snake venoms. This fold is characterized by three distinct loops rich in b-strands and emerging from a dense, globular core reticulated by four highly conserved disulfide bridges. The number and diversity of receptors, channels, and enzymes identified as targets of three-finger fold toxins is increasing continuously. Such manifold diversity highlights the specific adaptability of this fold for generating pleiotropic functions. Although this toxin superfamily disturbs many biological functions by interacting with a large diversity of molecular targets, the most significant target is the cholinergic system. By blocking the activity of the nicotinic and muscarinic acetylcholine receptors or by inhibiting the enzyme acetylcholinesterase, three-finger fold toxins interfere most drastically with neuromuscular junction functioning. Several of these toxins have become powerful pharmacological tools for studying the function and structure of their molecular targets. Most importantly, since dysfunction of these receptors/enzyme is involved in many diseases, exploiting the three-finger scaffold to create novel, highly specific therapeutic agents may represent a major future endeavor.

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Structural Insight into Specificity of Interactions between Nonconventional Three-finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors

Cited by 39 publications

References 46 publications

The Snake with the Scorpion’s Sting: Novel Three-Finger Toxin Sodium Channel Activators from the Venom of the Long-Glanded Blue Coral Snake (Calliophis bivirgatus)

The Snake with the Scorpion’s Sting: Novel Three-Finger Toxin Sodium Channel Activators from the Venom of the Long-Glanded Blue Coral Snake (Calliophis bivirgatus)

Structural Diversity and Dynamics of Human Three-Finger Proteins Acting on Nicotinic Acetylcholine Receptors

The three‐finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions

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