UniProt release 2017_04
Published April 12, 2017
Death (by insulin) in paradise
Have you ever been lucky enough to see cones snails in their natural habitat? Their shells are beautiful and you may be tempted to pick them up to admire them. Try to resist: cone snails hate that! These venomous animals can fire their harpoons and inject toxins under your skin. In some cases, these injections can be fatal. Cone snails produce 100-200 distinct venom peptides, and most of the characterized ones target their prey’s nervous system, including specific receptors, ion channels and transporters.
Cone snails predominantly live in warm seas and feed on fish, worms or molluscs. Fish-hunting cone snails can be classified into 2 categories depending upon their hunting strategy. There are ‘hook-and-line hunters’, who use a venomous harpoon, which is shot into the fish. There are ‘net hunters’, who protrude a sort of stretchy mouth, aim it at fish, and eventually engulf it. Cone snails move very slowly and all this process takes some time, so why does the fish not simply swim away? It has been proposed that cone snails release a subset of narcotizing or relaxing toxins, called the ‘nirvana cabal’, into water, causing fish to become disoriented and to stop moving.
The analysis of the Conus geographus venom gland transcriptome led to the amazing discovery of 3 transcripts (Con-Ins G1, Con-Ins G2 and Con-Ins G3), expressed at high levels and sharing very high homology with vertebrate insulin. The N-terminal half of Con-Ins G1 is almost identical to that of the fish hormone. It is known that the addition of human insulin to water causes hypoglycemia in fish, which severely affects their swimming behavior, insulin being absorbed via the gills. The effect can be reversed by placing fish in a 2% glucose bath. A similar effect was observed with synthetic Con-Ins G1, suggesting that it is indeed a component of the ‘nirvana cabal’.
Venom insulins are widely used by cone snails. All mollusc eaters produce venom insulins, as do many worm hunters, though not all. In fish hunters, all net hunters produce venom insulins, while hook-and-line do not. Venom insulins found in fish hunting cone snails closely resemble fish insulins, whereas those identified in snail-hunters share sequence and structural similarities with mollusc insulins. Interestingly, while cone snail insulin, produced in nerve rings to control their own glucose homeostasis, is highly conserved across all tested species, venom insulins diverge rapidly, suggesting adaptation to their specific prey.
Cone snail venom insulins are the smallest known insulins found in nature. They lack A- and B-chain C-terminal residues that, in vertebrates, are crucial for hormone storage and activity. In human pancreatic beta-cells, insulin is stored as a hexamer (a trimer of dimers), but it is the monomer that bears the hormonal activity. Hexamer-to-monomer conversion can cause a delay in insulin action that can lead to a delay in blood glucose control following insulin injection in diabetic patients. Attempts to shorten the C-terminus of human insulin B chain in order to abolish self-association have resulted in near-complete loss of activity. By contrast, Con-Ins G1 is monomeric, bypassing the hexamer conversion step, but it also potently binds to the human insulin receptor. It is yet not entirely clear how Con-Ins G1 achieves that. As most conotoxins, C. geographus insulins are extensively post-translationally modified. In the absence of modifications, insulin receptor activation is reduced by approximately 8-fold. The study of Con-Ins G1 crystal structure shows how Con-Ins G1 can compensate for the lack of C-terminal key residues, paving the way for the design of fast-acting therapeutic insulins.
The use of insulins in venoms has not been reported in any other animals, but cone snails. However, the Gila monster, a venomous lizard living in southwestern United States and northwestern Mexico, also targets the glucose homeostasis of its prey. It produces a peptide, called exendin-4, which mimics the incretin hormone glucagon-like peptide 1 (GLP-1), and acts as a potent stimulator of glucose-dependent insulin release. Exendin-4 has been developed as a commercial drug, under the name ‘Exenatide’, for the treatment of type 2 diabetes.
As of this release, the Con-Ins G1 entry is publicly available in the safe conotoxin-free environment of your computer.
Changes to the controlled vocabulary of human diseases
- Aortic aneurysm, familial thoracic 11
- Cerebroretinal microangiopathy with calcifications and cysts 2
- Ciliary dyskinesia, primary, 36, X-linked
- Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type
- Epileptic encephalopathy, early infantile, 51
- Epileptic encephalopathy, early infantile, 52
- Hyperparathyroidism 4
- Hypotonia, ataxia, and delayed development syndrome
- Intellectual developmental disorder with dysmorphic facies and ptosis
- Mental retardation, autosomal recessive 59
- Nemaline myopathy 11
- Yao syndrome
- Anterior segment mesenchymal dysgenesis -> Anterior segment dysgenesis 1
- Aphakia, congenital primary -> Anterior segment dysgenesis 2
- Iridogoniodysgenesis anomaly -> Anterior segment dysgenesis 3
- Iridogoniodysgenesis 2 -> Anterior segment dysgenesis 4
- Peters anomaly -> Anterior segment dysgenesis 5
- Methylmalonic aciduria type TCblR -> Methylmalonic aciduria, transient, due to transcobalamin receptor defect
- Corneal opacification with other ocular anomalies -> Anterior segment dysgenesis 7
- Congenital disorder of glycosylation 1Z -> Epileptic encephalopathy, early infantile, 50
- Ceroid lipofuscinosis, neuronal, 12