Disruption of Glucose Homeostasis in Prey: Combinatorial Use of Weaponized Mimetics of Somatostatin and Insulin by a Fish-Hunting Cone Snail

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Conus Geographus (geography Cone) (nubecula Geographus)

TISSUE(S): Venom

SUBMITTER: Thomas Koch  

LAB HEAD: Helena Safavi-Hemami

PROVIDER: PXD052869 | Pride | 2024-06-26

REPOSITORIES: Pride