Structural venomics reveals evolution of a complex venom by duplication and diversification of an ancient peptide-encoding gene

Abstract

<jats:p>Spiders are one of the most successful venomous animals, with more than 48,000 described species. Most spider venoms are dominated by cysteine-rich peptides with a diverse range of pharmacological activities. Some spider venoms contain thousands of unique peptides, but little is known about the mechanisms used to generate such complex chemical arsenals. We used an integrated transcriptomic, proteomic, and structural biology approach to demonstrate that the lethal Australian funnel-web spider produces 33 superfamilies of venom peptides and proteins. Twenty-six of the 33 superfamilies are disulfide-rich peptides, and we show that 15 of these are knottins that contribute &gt;90% of the venom proteome. NMR analyses revealed that most of these disulfide-rich peptides are structurally related and range in complexity from simple to highly elaborated knottin domains, as well as double-knot toxins, that likely evolved from a single ancestral toxin gene.</jats:p>

Complex precursor structures of cytolytic cupiennins identified in spider venom gland transcriptomes

“…The oldest strategy identified in mygalomorph spiders refers to the synthesis of hundreds of single, target specific neurotoxins, with targets usually being ion channels. Recruitment of a single ancestral DDH and/or ICK gene into the venom gland of the Australian funnel web spiders, followed by multiple gene duplications, diversification, and selection of neurotoxins by adaptive evolution, but also intragene duplications, are the key for the production of such neurotoxins 29 . This implies high metabolic costs for the spider, as one peptide precursor results in only one specific mature neurotoxin, for one specific target.…”

Animal toxins — Nature’s evolutionary-refined toolkit for basic research and drug discovery

“…More recently, the spider-venom peptide Hi1a was shown to inhibit larval development of the barber's pole worm Haemonchus contortus, a parasite of sheep production [210]. Gomesin, a peptide found in the venom [211] and hemocytes [212] of spiders, has broad-spectrum activity against bacteria, fungi, parasites and tumor cells [213,214], and a cyclized version was recently shown to have improved stability and activity against Plasmodium in vitro [215].…”

Deadly Proteomes: A Practical Guide to Proteotranscriptomics of Animal Venoms

“…For example, snake venoms tend to be relatively simple with respect to the total number and diversity of toxins, as well as the range of PTMs, but contain a higher proportion of large polypeptides and enzymes. [39] In contrast, the venoms of spiders and cone snails can contain hundreds of small peptides spread across dozens of peptide superfamilies, [76,111] and these peptides often have PTMs. While modification of spider-venom peptides is mostly limited to common PTMs such as disulfide bridges and C-terminal amidation, cone snails are the masters of exotic PTMs.…”