Project description:Peptide hormones and neuropeptides form a diverse class of signaling molecules that control essential processes in animals. Despite several breakthroughs in peptide discovery, many signaling peptides remain undiscovered. Recently, we demonstrated the use of somatostatin-like toxins from cone snail venom to identify homologous signaling peptides in prey. Here, we demonstrate that this toxin-based approach can be systematically applied to the discovery of other unknown bilaterian signaling peptides. Using large sequencing datasets, we searched for homologies between cone snail toxins and putative peptides from several important model organisms representing the snails’ prey. We identified and confirmed expression of five toxin families that share strong similarities with previously unknown signaling peptides from mollusks and annelids. One of the peptides was also identified in rotifers, brachiopods, platyhelminths, and arthropods, and another was found to be structurally related to crustacean hyperglycemic hormone, a peptide not previously known to exist in Spiralia. Based on several lines of evidence we propose that these signaling peptides not only exist but serve important physiological functions. Finally, we propose that the discovery pipeline developed here can be more broadly applied to other systems in which one organism has evolved molecules to manipulate the physiology of another.
Project description:Peptide hormones and neuropeptides form a diverse class of signaling molecules that control essential processes in animals. Despite several breakthroughs in peptide discovery, many signaling peptides remain undiscovered. Recently, we demonstrated the use of somatostatin-like toxins from cone snail venom to identify homologous signaling peptides in prey. Here, we demonstrate that this toxin-based approach can be systematically applied to the discovery of other unknown bilaterian signaling peptides. Using large sequencing datasets, we searched for homologies between cone snail toxins and putative peptides from several important model organisms representing the snails’ prey. We identified and confirmed expression of five toxin families that share strong similarities with previously unknown signaling peptides from mollusks and annelids. One of the peptides was also identified in rotifers, brachiopods, platyhelminths, and arthropods, and another was found to be structurally related to crustacean hyperglycemic hormone, a peptide not previously known to exist in Spiralia. Based on several lines of evidence we propose that these signaling peptides not only exist but serve important physiological functions. Finally, we propose that the discovery pipeline developed here can be more broadly applied to other systems in which one organism has evolved molecules to manipulate the physiology of another.
Project description:Peptide hormones and neuropeptides form a diverse class of signaling molecules that control essential processes in animals. Despite several breakthroughs in peptide discovery, many signaling peptides remain undiscovered. Recently, we demonstrated the use of somatostatin-like toxins from cone snail venom to identify homologous signaling peptides in prey. Here, we demonstrate that this toxin-based approach can be systematically applied to the discovery of other unknown bilaterian signaling peptides. Using large sequencing datasets, we searched for homologies between cone snail toxins and putative peptides from several important model organisms representing the snails’ prey. We identified and confirmed expression of five toxin families that share strong similarities with previously unknown signaling peptides from mollusks and annelids. One of the peptides was also identified in rotifers, brachiopods, platyhelminths, and arthropods, and another was found to be structurally related to crustacean hyperglycemic hormone, a peptide not previously known to exist in Spiralia. Based on several lines of evidence we propose that these signaling peptides not only exist but serve important physiological functions. Finally, we propose that the discovery pipeline developed here can be more broadly applied to other systems in which one organism has evolved molecules to manipulate the physiology of another.
Project description:Venomous animals have evolved diverse molecular mechanisms to incapacitate prey and defend against predators. The majority of venom components characterized to date disrupt the nervous, locomotor, and cardiovascular system or causes tissue damage and degradation. The discovery that certain species of fish-hunting cone snail use weaponized insulins to induce hypoglycemic shock in prey provided an unusual example for the use of toxins that target glucose homeostasis. Here, we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective agonist of the somatostatin receptor 2 (SSTR2) that potently blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms that contain a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin’s N-terminal tail aligns with a glycosylated somatostatin peptide previously identified from fish pancreas and plays an important role in activating the fish SSTR2. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.
Project description:Venomous animals have evolved diverse molecular mechanisms to incapacitate prey and defend against predators. The majority of venom components characterized to date disrupt the nervous, locomotor, and cardiovascular system or causes tissue damage and degradation1. The discovery that certain species of fish-hunting cone snail use weaponized insulins to induce hypoglycemic shock in prey provided an unusual example for the use of toxins that target glucose homeostasis2. Here, we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective agonist of the somatostatin receptor 2 (SSTR2) that potently blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms that contain a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin’s N-terminal tail aligns with a glycosylated somatostatin peptide previously identified from fish pancreas and plays an important role in activating the fish SSTR2. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.