Our study dragging Heloderma venom out of the dark ages has finally been published

Despite a state of fame that extends far beyond the fields of herpetology and natural history, Heloderma suspectum ssp (Gila Monsters) and Heloderma horridum ssp Mexican (Beaded Lizards) have remained remarkably enigmatic animals. In particular, the evolution of their venom system has remained controversial, mainly due to their secretive ecology and persistent folkloristic misconceptions that strongly influenced earlier scientific reports. Misunderstandings persist even today. For example the therapeutically useful exendin peptide toxins (marketed under the diabetes drug name Byetta) have been erroneously referred to as originating from the ‘saliva’ when they have in fact only ever been isolated from venom and mRNA coding for these specific compounds only ever recovered from the venom gland.

We used nterdisciplinary techniques were to investigate the inter-play between organismal evolution and venom system diversification in helodermatid lizards. It was revealed that:

1) that there is a strong genetic division between the species and subdivision within these endangered species, with Heloderma horridum being significantly genetically complex to the point of multiple species level divisions
2) the morphology of the venom gland is different between H. horridum and H. suspectum, pointing to an active and on-going diversification parallel to organismal evolution
3) reflective of venom gland changes, over-all these two species have different venom compositions
4) transcriptome profiling of the venom gland has identified novel venom components either unique to Heloderma or not previously known to be in Heloderma venoms
5) bioactivity characterization revealed different effects between the two Heloderma species, contributing to our understanding of toxin structure-function relationships.

Molecular analyses also revealed three novel domain utilisation strategies unique to the molecular evolution of helodermatid venom toxins:
i) an ancestral tri-domain gene being cleaved into two new, independently evolving, mono-domain genes (exendin peptides)
ii) an ancestral mono-domain gene (natriuretic) being mutated to additionally encode four new tandemly repeated upstream novel peptides (helokinestatin) with post-translational proteolysis liberating the five discrete peptides
iii) an ancestral mono-domain gene (beta-defensin) being tandemly repeated to encode for a new single product with a possible novel protein fold (Lethal Toxin).

Further, helodermatid venom PLA2 toxins were shown to undergo post-translational processing to remove a significant stretch of C-terminal residues. These results highlight the importance of utilising evolutionary-based search strategies for biodiscovery.

I have made the paper freely downloadable to anyone who wants to read it. The link to the PDF is below.

Cheers
Bryan


Novel Venom Proteins Produced by Differential Domain-Expression Strategies in Beaded Lizards and Gil


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Dr. Bryan Grieg Fry
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Venomics Research Laboratory,
Department of Biochemistry,
Bio21 Institute,
University of Melbourne
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http://www.venomdoc.com

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