Rattlesnake protein provides anti-venom clues

Many poisonous snakes are resistant to their own venom, but researchers don’t know how or why. Now, scientists have solved this biochemical mystery in a type of rattlesnake called the western diamondback. In this snake, a single inhibitor acts against a slew of venom molecules (Proc. Natl. Acad. Sci. U.S.A. 2022, DOI: 10.1073/pnas.2214880119).

One key component in rattlesnakes’ venom is a class of molecules called metalloproteinases, which degrade collagen in connective tissue and break down blood vessels and blood clots, causing hemorrhage. Sean B. Carroll and his colleagues at the University of Maryland focused on the western diamondback because its genome encodes 30 metalloproteinases, more than any other known rattlesnake genome. To their surprise, one of the snake’s five metalloproteinase inhibitors can inhibit different classes of venom molecules, binding “essentially all the ones in the venom,” Carroll says. This protein, called FETUA-3, is present in the diamondback’s Asian and South American rattlesnake relatives, but surprisingly doesn’t broadly protect against venom molecules in those animals–a different inhibitor does that job. This suggests that the two inhibitors somehow evolved species-specificity.

The ability of a single protein to neutralize an entire class of toxins is “intriguing from an antivenom point of view,” says Carroll. The venom contains other toxins that would need to be disabled, but FETUA-3 “can certainly be an interesting ingredient” in a potential therapeutic for counteracting rattlesnake bites.