title: Short toxin-like proteins attack the defense line of innate immunity.
abstract: ClanTox (classifier of animal toxins) was developed for identifying toxin-like candidates from complete proteomes. Searching mammalian proteomes for short toxin-like proteins (coined TOLIPs) revealed a number of overlooked secreted short proteins with an abundance of cysteines throughout their sequences. We applied bioinformatics and data-mining methods to infer the function of several top predicted candidates. We focused on cysteine-rich peptides that adopt the fold of the three-finger proteins (TFPs). We identified a cluster of duplicated genes that share a structural similarity with elapid neurotoxins, such as α-bungarotoxin. In the murine proteome, there are about 60 such proteins that belong to the Ly6/uPAR family. These proteins are secreted or anchored to the cell membrane. Ly6/uPAR proteins are associated with a rich repertoire of functions, including binding to receptors and adhesion. Ly6/uPAR proteins modulate cell signaling in the context of brain functions and cells of the innate immune system. We postulate that TOLIPs, as modulators of cell signaling, may be associated with pathologies and cellular imbalance. We show that proteins of the Ly6/uPAR family are associated with cancer diagnosis and malfunction of the immune system.
authors.affiliation: Department of Biological Chemistry, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. yitshak.tirosh@mail.huji.ac.il
authors.forename: Yitshak
authors.initials: Y
authors.lastname: Tirosh
authors.forename: Dan
authors.initials: D
authors.lastname: Ofer
authors.forename: Tsiona
authors.initials: T
authors.lastname: Eliyahu
authors.forename: Michal
authors.initials: M
authors.lastname: Linial
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D009369:Neoplasms / Q000175:diagnosis; D009498:Neurotoxins / Q000633:toxicity*; D011487:Protein Conformation; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D012910:Snake Venoms / Q000633:toxicity*; D059467:Transcriptome; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; C526827:Ly6 protein, mouse; D009498:Neurotoxins; D020543:Proteome; D012910:Snake Venoms; D014568:Urokinase-Type Plasminogen Activator