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Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates

Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands
Toxin Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, Australia
Australian National Insect Collection, Commonwealth Science & Industry Research Organisation, Acton, ACT 2601, Australia
Department of Molecular and Biomedical Sciences, Josef Stefan Institute, 1000 Ljubljana, Slovenia
Division of BioAnalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
Australian Venom Research Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC 3010, Australia
Naturalis Biodiversity Center Leiden, 2333 CR Leiden, The Netherlands
Department of Biological Science, National University of Singapore, Singapore 117543, Singapore
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
Department of Microbiology, University of Veterinary and Animal Sciences, Lahore 54000, Pakistan
Treidlia Biovet, 36/45 Powers Road, Seven Hills, NSW 2147, Australia
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors are joint corresponding authors.
Received: 12 August 2020 / Revised: 19 September 2020 / Accepted: 22 September 2020 / Published: 2 October 2020
(This article belongs to the Special Issue Using Genomics to Understand Venom Evolution)
Venomous snakes are important subjects of study in evolution, ecology, and biomedicine. Many venomous snakes have alpha-neurotoxins (α-neurotoxins) in their venom. These toxins bind the alpha-1 nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction, causing paralysis and asphyxia. Several venomous snakes and their predators have evolved resistance to α-neurotoxins. The resistance is conferred by steric hindrance from N-glycosylated asparagines at amino acids 187 or 189, by an arginine at position 187 that has been hypothesized to either electrostatically repulse positively charged neurotoxins or sterically interfere with α-neurotoxin binding, or proline replacements at positions 194 or 197 of the nAChR ligand-binding domain to inhibit α-neurotoxin binding through structural changes in the receptor. Here, we analyzed this domain in 148 vertebrate species, and assessed its amino acid sequences for resistance-associated mutations. Of these sequences, 89 were sequenced de novo. We find widespread convergent evolution of the N-glycosylation form of resistance in several taxa including venomous snakes and their lizard prey, but not in the snake-eating birds studied. We also document new lineages with the arginine form of inhibition. Using an in vivo assay in four species, we provide further evidence that N-glycosylation mutations reduce the toxicity of cobra venom. The nAChR is of crucial importance for normal neuromuscular function and is highly conserved throughout the vertebrates as a result. Our research shows that the evolution of α-neurotoxins in snakes may well have prompted arms races and mutations to this ancient receptor across a wide range of sympatric vertebrates. These findings underscore the inter-connectedness of the biosphere and the ripple effects that one adaption can have across global ecosystems. View Full-Text
Keywords: evolutionary arms race; Elapidae; venom; resistance; nicotinic acetylcholine receptor (nAChR); CHRNA1; N-glycosylation evolutionary arms race; Elapidae; venom; resistance; nicotinic acetylcholine receptor (nAChR); CHRNA1; N-glycosylation
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MDPI and ACS Style

Khan, M.A.; Dashevsky, D.; Kerkkamp, H.; Kordiš, D.; de Bakker, M.A.G.; Wouters, R.; van Thiel, J.; op den Brouw, B.; Vonk, F.J.; Kini, R.M.; Nazir, J.; Fry, B.G.; Richardson, M.K. Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates. Toxins 2020, 12, 638.

AMA Style

Khan MA, Dashevsky D, Kerkkamp H, Kordiš D, de Bakker MAG, Wouters R, van Thiel J, op den Brouw B, Vonk FJ, Kini RM, Nazir J, Fry BG, Richardson MK. Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates. Toxins. 2020; 12(10):638.

Chicago/Turabian Style

Khan, Muzaffar A.; Dashevsky, Daniel; Kerkkamp, Harald; Kordiš, Dušan; de Bakker, Merijn A.G.; Wouters, Roel; van Thiel, Jory; op den Brouw, Bianca; Vonk, Freek J.; Kini, R. M.; Nazir, Jawad; Fry, Bryan G.; Richardson, Michael K. 2020. "Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates" Toxins 12, no. 10: 638.

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