title: A sodium channel inhibitor ISTX-I with a novel structure provides a new hint at the evolutionary link between two toxin folds.
abstract: Members of arachnida, such as spiders and scorpions, commonly produce venom with specialized venom glands, paralyzing their prey with neurotoxins that specifically target ion channels. Two well-studied motifs, the disulfide-directed hairpin (DDH) and the inhibitor cystine knot motif (ICK), are both found in scorpion and spider toxins. As arachnids, ticks inject a neurotoxin-containing cocktail from their salivary glands into the host to acquire a blood meal, but peptide toxins acting on ion channels have not been observed in ticks. Here, a new neurotoxin (ISTX-I) that acts on sodium channels was identified from the hard tick Ixodes scapularis and characterized. ISTX-I exhibits a potent inhibitory function with an IC50 of 1.6 μM for sodium channel Nav1.7 but not other sodium channel subtypes. ISTX-I adopts a novel structural fold and is distinct from the canonical ICK motif. Analysis of the ISTX-I, DDH and ICK motifs reveals that the new ISTX-I motif might be an intermediate scaffold between DDH and ICK, and ISTX-I is a clue to the evolutionary link between the DDH and ICK motifs. These results provide a glimpse into the convergent evolution of neurotoxins from predatory and blood-sucking arthropods.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences &Yunnan Province, Kunming Institute of Zoology, Kunming Yunnan 650223, China.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Rong
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
authors.forename: Jiangxin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences &Yunnan Province, Kunming Institute of Zoology, Kunming Yunnan 650223, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Life Sciences College of Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
authors.forename: Gan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Yunnan Academy of Grassland and Animal Science, Xiaoshao, Kunming 650212, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, and Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, and Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Hu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences &Yunnan Province, Kunming Institute of Zoology, Kunming Yunnan 650223, China.|Life Sciences College of Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Lai
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001180:Arthropod Venoms / Q000737:chemistry / Q000633:toxicity; D019143:Evolution, Molecular; D057809:HEK293 Cells; D006801:Humans; D018884:Ixodes / Q000737:chemistry*; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000633:toxicity
chemical_list: D001180:Arthropod Venoms; D062556:NAV1.7 Voltage-Gated Sodium Channel; C503480:Scn9a protein, rat; D026941:Sodium Channel Blockers