The primordial knot: the deep-rooted origin of the disulfide-rich spider venom toxins

Abstract

Spider venoms are a complex concoction of enzymes, polyamines, inorganic salts and disulfide-rich peptides (DRPs). Although DRPs are widely distributed and abundant, their evolutionary origin has remained elusive. This knowledge gap stems from the extensive molecular divergence of DRPs and a lack of sequence and structural data from diverse lineages. By evaluating DRPs under a comprehensive phylogenetic, structural and evolutionary framework, we have not only identified over 70 novel spider toxin superfamilies but also provide the first evidence for their common origin. We trace the origin of these toxin superfamilies to a primordial knot - the Adi Shakti - nearly [~]375 MYA in the common ancestor of Araneomorphae and Mygalomorphae. As these lineages constitute over 50% of the extant spiders, our findings provide fascinating insights into the early evolution and diversification of the spider venom arsenal. Reliance on a single molecular toxin scaffold by nearly all spiders is in complete contrast to most other venomous animals that have recruited into their venoms diverse toxins with independent origins. Moreover, by comparatively evaluating araneomorph and mygalomorph spiders that differentially depend on their ability to secrete silk for prey capture, we highlight the prominent role of predatory strategies in driving the evolution of spider venom. Significance StatementVenoms are concoctions of biochemicals that function in concert to incapacitate prey or predators of venom-producing animals. Most venomous animals secrete a complex venom cocktail, constituted by toxins with independent evolutionary origins. In complete contrast, we trace the origin of diverse toxin superfamilies in spiders to a single molecular scaffold. The common origin of these disulphide-rich peptides that constitute three-quarters of nearly all spider venoms, therefore, represents a unique scenario of weaponization, where a single motif was recruited and extensively diversified to generate a plethora of superfamilies with distinct activities. Remarkably, the evolution of spider venom was also found to be driven by prey capture (i.e., reliance on silk versus venom) and venom deployment (predation or self-defence) strategies.