Most animal toxins are short proteins that appear in venom and vary in sequence, structure and function. A common characteristic of many such toxins is their apparent structural stability. Sporadic instances of endogenous toxin-like proteins that function in non-venom context have been reported. We have utilized machine learning methodology, based on sequence-derived features and guided by the notion of structural stability, in order to conduct a large-scale search for toxin and toxin-like proteins. Application of the method to insect and mammalian sequences revealed novel families of toxin-like proteins. One of these proteins shows significant similarity to ion channel inhibitors that are expressed in cone snail and assassin bug venom, and is surprisingly expressed in the bee brain. A toxicity assay in which the protein was injected to fish induced a strong yet reversible paralytic effect. We suggest that the protein may function as an endogenous modulator of voltage-gated Ca2+ channels. Additionally, we have identified a novel mammalian cluster of toxin-like proteins that are expressed in the testis. We suggest that these proteins might be involved in regulation of nicotinic acetylcholine receptors that affect the acrosome reaction and sperm motility. Finally, we highlight a possible evolutionary link between venom toxins and antibacterial proteins. We expect our methodology to enhance the discovery of additional novel protein families.
Bibliographical noteFunding Information:
We are grateful to Daniel Sher (Dr Zlotkin laboratory, the Hebrew University) for his advice and support. Injections in insects and fish were conducted by D. Sher. We thank Alex Inberg for mass spectrometry support and Alomone laboratories (Jerusalem) for support and advice. N.K. received a fellowship from the Sudarsky Center for Computational Biology. This study was supported by the EU Framework VI NoE BioSapiens and DIAMONDS.
- genome annotation
- short proteins