{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T15:40:05Z","timestamp":1772638805646,"version":"3.50.1"},"reference-count":118,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2013,12,13]],"date-time":"2013-12-13T00:00:00Z","timestamp":1386892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>The episodic nature of natural selection and the accumulation of extreme sequence divergence in venom-encoding genes over long periods of evolutionary time can obscure the signature of positive Darwinian selection. Recognition of the true biocomplexity is further hampered by the limited taxon selection, with easy to obtain or medically important species typically being the subject of intense venom research, relative to the actual taxonomical diversity in nature. This holds true for scorpions, which are one of the most ancient terrestrial venomous animal lineages. The family Buthidae that includes all the medically significant species has been intensely investigated around the globe, while almost completely ignoring the remaining non-buthid families. Australian scorpion lineages, for instance, have been completely neglected, with only a single scorpion species (Urodacus yaschenkoi) having its venom transcriptome sequenced. Hence, the lack of venom composition and toxin sequence information from an entire continent\u2019s worth of scorpions has impeded our understanding of the molecular evolution of scorpion venom. The molecular origin, phylogenetic relationships and evolutionary histories of most scorpion toxin scaffolds remain enigmatic. In this study, we have sequenced venom gland transcriptomes of a wide taxonomical diversity of scorpions from Australia, including buthid and non-buthid representatives. Using state-of-art molecular evolutionary analyses, we show that a majority of CS\u03b1\/\u03b2 toxin scaffolds have experienced episodic influence of positive selection, while most non-CS\u03b1\/\u03b2 linear toxins evolve under the extreme influence of negative selection. For the first time, we have unraveled the molecular origin of the major scorpion toxin scaffolds, such as scorpion venom single von Willebrand factor C-domain peptides (SV-SVC), inhibitor cystine knot (ICK),  disulphide-directed beta-hairpin (DDH), bradykinin potentiating peptides (BPP), linear non-disulphide bridged peptides and antimicrobial peptides (AMP). We have thus demonstrated that even neglected lineages of scorpions are a rich pool of novel biochemical components, which have evolved over millions of years to target specific ion channels in prey animals, and as a result, possess tremendous implications in therapeutics.<\/jats:p>","DOI":"10.3390\/toxins5122456","type":"journal-article","created":{"date-parts":[[2013,12,16]],"date-time":"2013-12-16T06:18:40Z","timestamp":1387174720000},"page":"2456-2487","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Evolution Stings: The Origin and Diversification of Scorpion Toxin Peptide Scaffolds"],"prefix":"10.3390","volume":"5","author":[{"given":"Kartik","family":"Sunagar","sequence":"first","affiliation":[{"name":"CIMAR\/CIIMAR, Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Universidade do Porto, Rua dos Bragas, 177, 4050-123 Porto, Portugal"},{"name":"Departamento de Biologia, Faculdade de Ci\u00eancias, Universidade do Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal"}]},{"given":"Eivind","family":"Undheim","sequence":"additional","affiliation":[{"name":"Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia"},{"name":"Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia"}]},{"given":"Angelo","family":"Chan","sequence":"additional","affiliation":[{"name":"Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia"}]},{"given":"Ivan","family":"Koludarov","sequence":"additional","affiliation":[{"name":"Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia"},{"name":"Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia"}]},{"given":"Sergio","family":"Mu\u00f1oz-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Centre for Comparative Genomics and Evolutionary Bioinformatics, Dalhousie University, Halifax, Nova Scotia, Canada"}]},{"given":"Agostinho","family":"Antunes","sequence":"additional","affiliation":[{"name":"CIMAR\/CIIMAR, Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Universidade do Porto, Rua dos Bragas, 177, 4050-123 Porto, Portugal"},{"name":"Departamento de Biologia, Faculdade de Ci\u00eancias, Universidade do Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6661-1283","authenticated-orcid":false,"given":"Bryan","family":"Fry","sequence":"additional","affiliation":[{"name":"Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia"},{"name":"Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia"}]}],"member":"1968","published-online":{"date-parts":[[2013,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1093\/molbev\/mss058","article-title":"Evolution of CRISPs associated with toxicoferan-reptilian venom and mammalian reproduction","volume":"29","author":"Sunagar","year":"2012","journal-title":"Mol. Biol. Evol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1074\/mcp.M112.023135","article-title":"Differential evolution and neofunctionalization of snake venom metalloprotease domains","volume":"12","author":"Brust","year":"2013","journal-title":"Mol. Cell. Proteomics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1093\/molbev\/msr091","article-title":"Domain loss facilitates accelerated evolution and neofunctionalization of duplicate snake venom metalloproteinase toxin genes","volume":"28","author":"Casewell","year":"2011","journal-title":"Mol. Biol. Evol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s00239-003-2461-2","article-title":"Molecular evolution and phylogeny of elapid snake venom three-finger toxins","volume":"57","author":"Fry","year":"2003","journal-title":"J. Mol. Evol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fry, B.G., Scheib, H., Weerd, L. Van Der, Young, B., Mcnaughtan, J., Ramjan, S.F.R., Vidal, N., Poelmann, R.E., and Norman, J.A. (2008). Evolution of an Arsenal. Mol. Cell. Proteomics, 14\u201318.","DOI":"10.1074\/mcp.M700094-MCP200"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0378-1119(00)00490-X","article-title":"Adaptive evolution of animal toxin multigene families","volume":"261","author":"Kordis","year":"2000","journal-title":"Gene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s00239-010-9321-7","article-title":"Evolution of Conus peptide genes: duplication and positive selection in the A-superfamily","volume":"70","author":"Puillandre","year":"2010","journal-title":"J. Mol. Evol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/molbev\/msp310","article-title":"Positions under positive selection--key for selectivity and potency of scorpion alpha-toxins","volume":"27","author":"Weinberger","year":"2010","journal-title":"Mol. Biol. Evol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1371\/journal.pone.0005558","article-title":"Ecological Release and Venom Evolution of a Predatory Marine Snail at Easter Island","volume":"4","author":"Duda","year":"2009","journal-title":"PLoS One"},{"key":"ref_10","first-page":"2443","article-title":"Coevolution of diet and prey-specific venom activity supports the role of selection in snake venom evolution","volume":"276","author":"Barlow","year":"2009","journal-title":"Proc. Biol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/379537a0","article-title":"Diet and snake venom evolution","volume":"379","author":"Daltry","year":"1996","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jprot.2013.05.034","article-title":"Dracula\u2019s children: Molecular evolution of vampire bat venom","volume":"89","author":"Low","year":"2013","journal-title":"J. Proteomics"},{"key":"ref_13","unstructured":"Kastin, A.J. (2013). Handbook of Biologically Active Peptides, Elsevier. [2nd ed.]."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s10493-009-9247-1","article-title":"Calibrating the chelicerate clock: a paleontological reply to Jeyaprakash and Hoy","volume":"48","author":"Dunlop","year":"2009","journal-title":"Exp. Appl. Acarol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e52822","DOI":"10.1371\/journal.pone.0052822","article-title":"As Old as the hills: montane scorpions in Southwestern North America reveal ancient associations between biotic diversification and landscape history","volume":"8","author":"Bryson","year":"2013","journal-title":"PLoS One"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e68282","DOI":"10.1371\/journal.pone.0068282","article-title":"Species Delimitation and Morphological Divergence in the Scorpion Centruroides vittatus (Say, 1821): Insights from Phylogeography","volume":"8","author":"Yamashita","year":"2013","journal-title":"PLoS One"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1126\/science.249.4973.1176","article-title":"The Biology of Scorpions. Gary A. Polis, Ed. Stanford University Press, Stanford, CA, 1990. xxvi, 587 pp., illus. $85","volume":"249","author":"Zeh","year":"1990","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1055-7903(03)00031-9","article-title":"The phylogeographic importance of the Strait of Gibraltar as a gene flow barrier in terrestrial arthropods: a case study with the scorpion Buthus occitanus as model organism","volume":"28","author":"Gantenbein","year":"2003","journal-title":"Mol. Phylogenet. Evol."},{"key":"ref_19","unstructured":"Polis, G.A. (1990). The Biology of Scorpions, Stanford University Press."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S0300-9084(00)01167-6","article-title":"Peptides and genes coding for scorpion toxins that affect ion-channels","volume":"82","author":"Possani","year":"2001","journal-title":"Biochimie"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.toxicon.2006.09.022","article-title":"Voltage-gated ion channels and gating modifier toxins","volume":"49","author":"Catterall","year":"2007","journal-title":"Toxicon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.toxicon.2009.11.010","article-title":"Mining on scorpion venom biodiversity","volume":"56","author":"Schwartz","year":"2010","journal-title":"Toxicon"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.toxicon.2012.04.337","article-title":"Spider-venom peptides that target voltage-gated sodium channels: Pharmacological tools and potential therapeutic leads","volume":"60","author":"Klint","year":"2012","journal-title":"Toxicon"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Quintero-Hern\u00e1ndez, V., Jim\u00e9nez-Vargas, J.M., Gurrola, G.B., Valdivia, H.H., and Possani, L.D. (2013). Scorpion venom components that affect ion-channels function. Toxicon.","DOI":"10.1016\/j.toxicon.2013.07.012"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1271\/bbb.90723","article-title":"A novel amphipathic linear peptide with both insect toxicity and antimicrobial activity from the venom of the scorpion Isometrus maculatus","volume":"74","author":"Miyashita","year":"2010","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.peptides.2011.11.012","article-title":"Characterization of BmKbpp, a multifunctional peptide from the Chinese scorpion Mesobuthus martensii Karsch: gaining insight into a new mechanism for the functional diversification of scorpion venom peptides","volume":"33","author":"Zeng","year":"2012","journal-title":"Peptides"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1186\/1471-2164-11-452","article-title":"Comparative venom gland transcriptome analysis of the scorpion Lychas mucronatus reveals intraspecific toxic gene diversity and new venomous components","volume":"11","author":"Ruiming","year":"2010","journal-title":"BMC Genomics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.peptides.2012.04.010","article-title":"StCT2, a new antibacterial peptide characterized from the venom of the scorpion Scorpiops tibetanus","volume":"36","author":"Cao","year":"2012","journal-title":"Peptides"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.peptides.2012.02.002","article-title":"Gene cloning and functional characterization of four novel antimicrobial-like peptides from scorpions of the family Vaejovidae","volume":"34","author":"Corzo","year":"2012","journal-title":"Peptides"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.peptides.2012.03.016","article-title":"Antimicrobial\/cytolytic peptides from the venom of the North African scorpion, Androctonus amoreuxi: Biochemical and functional characterization of natural peptides and a single site-substituted analog","volume":"35","author":"Almaaytah","year":"2012","journal-title":"Peptides"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.peptides.2010.10.008","article-title":"A new natural \u03b1-helical peptide from the venom of the scorpion Heterometrus petersii kills HCV","volume":"32","author":"Yan","year":"2011","journal-title":"Peptides"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.peptides.2003.12.003","article-title":"Identification and functional characterization of novel scorpion venom peptides with no disulfide bridge from Buthus martensii Karsch","volume":"25","author":"Zeng","year":"2004","journal-title":"Peptides"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.1128\/AAC.00542-08","article-title":"Mucroporin, the first cationic host defense peptide from the venom of Lychas mucronatus","volume":"52","author":"Dai","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5220","DOI":"10.1128\/AAC.00369-11","article-title":"Ctriporin, a New Anti-Methicillin-Resistant Staphylococcus aureus Peptide from the Venom of the Scorpion Chaerilus tricostatus","volume":"55","author":"Fan","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/pmic.201100409","article-title":"Molecular diversity of the telson and venom components from Pandinus cavimanus (Scorpionidae Latreille 1802): Transcriptome, venomics and function","volume":"12","author":"Peigneur","year":"2012","journal-title":"Proteomics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1016\/j.peptides.2005.06.008","article-title":"Genomic organization of four novel nondisulfide-bridged peptides from scorpion Mesobuthus martensii Karsch: gaining insight into evolutionary mechanism","volume":"26","author":"Luo","year":"2005","journal-title":"Peptides"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.toxicon.2004.10.014","article-title":"The Brazilian scorpion Tityus costatus Karsch: genes, peptides and function","volume":"45","author":"Batista","year":"2005","journal-title":"Toxicon"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.biochi.2009.05.005","article-title":"Molecular cloning and nucleotide sequence analysis of genes from a cDNA library of the scorpion Tityus discrepans","volume":"91","author":"Schwartz","year":"2009","journal-title":"Biochimie"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.toxicon.2005.09.006","article-title":"Overview of scorpion toxins specific for Na+ channels and related peptides: biodiversity, structure-function relationships and evolution","volume":"46","author":"Possani","year":"2005","journal-title":"Toxicon"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1111\/j.1432-1033.2004.04181.x","article-title":"NMR solution structure of Cn12, a novel peptide from the Mexican scorpion Centruroides noxius with a typical \u03b2-toxin sequence but with \u03b1-like physiological activity","volume":"271","author":"Pimienta","year":"2004","journal-title":"Eur. J. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/S0014-5793(01)02336-5","article-title":"Evidence for a position-specific deletion as an evolutionary link between long- and short-chain scorpion toxins","volume":"494","author":"Bougis","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/j.peptides.2006.01.012","article-title":"Molecular dissection of venom from Chinese scorpion Mesobuthus martensii: identification and characterization of four novel disulfide-bridged venom peptides","volume":"27","author":"Zeng","year":"2006","journal-title":"Peptides"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"572","DOI":"10.2741\/4121","article-title":"Scorpion beta-toxins and voltage-gated sodium channels: interactions and effects","volume":"18","author":"Possani","year":"2013","journal-title":"Front. Biosci. Landmark"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.peptides.2006.06.012","article-title":"Wide phylogenetic distribution of Scorpine and long-chain beta-KTx-like peptides in scorpion venoms: identification of \u201corphan\u201d components","volume":"28","author":"Schwartz","year":"2007","journal-title":"Peptides"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00018-007-7370-x","article-title":"Cytolytic and K+ channel blocking activities of beta-KTx and scorpine-like peptides purified from scorpion venoms","volume":"65","author":"Schwartz","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.toxicon.2007.04.012","article-title":"Characterization of peptide components in the venom of the scorpion Liocheles australasiae (Hemiscorpiidae)","volume":"50","author":"Miyashita","year":"2007","journal-title":"Toxicon"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.peptides.2012.10.004","article-title":"Molecular and bioinformatical characterization of a novel superfamily of cysteine-rich peptides from arthropods","volume":"41","author":"Zeng","year":"2013","journal-title":"Peptides"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.toxicon.2009.04.010","article-title":"Cloning and characterization of cDNA sequences encoding for new venom peptides of the Brazilian scorpion Opisthacanthus cayaporum","volume":"54","author":"Silva","year":"2009","journal-title":"Toxicon"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Gao, B., Harvey, P.P.J., Craik, D.D.J., Ronjat, M., De Waard, M., and Zhu, S. (2013). Functional evolution of scorpion venom peptides with an inhibitor cystine knot fold. Biosci. Rep., 33.","DOI":"10.1042\/BSR20130052"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1111\/j.1476-5381.2009.00147.x","article-title":"Characterization of hadrucalcin, a peptide from Hadrurus gertschi scorpion venom with pharmacological activity on ryanodine receptors","volume":"157","author":"Schwartz","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_51","first-page":"2631","article-title":"Hadrucalcin, a novel member of the Calcin scorpion toxin family, rapidly penetrates cellular membranes to bind ryanodine receptors and alter calcium release","volume":"94","author":"Capes","year":"2008","journal-title":"J. Biophys."},{"key":"ref_52","first-page":"1765","article-title":"Evolutionary origin of inhibitor cystine knot peptides","volume":"17","author":"Zhu","year":"2003","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0014-5793(97)00227-5","article-title":"Primary structure and synthesis of Imperatoxin A (IpTx(a)), a peptide activator of Ca2+ release channels\/ryanodine receptors","volume":"405","author":"Zamudio","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12185","DOI":"10.1073\/pnas.89.24.12185","article-title":"Scorpion toxins targeted against the sarcoplasmic reticulum Ca(2+)-release channel of skeletal and cardiac muscle","volume":"89","author":"Valdivia","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1085\/jgp.111.5.679","article-title":"Imperatoxin A Induces Subconductance States in Ca2+ Release Channels (Ryanodine Receptors) of Cardiac and Skeletal Muscle","volume":"111","author":"Tripathy","year":"1998","journal-title":"J. Gen. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/S0006-3495(02)75487-8","article-title":"Imperatoxin a enhances Ca(2+) release in developing skeletal muscle containing ryanodine receptor type 3","volume":"82","author":"Nabhani","year":"2002","journal-title":"Biophys. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1042\/bj20031192","article-title":"Il Molecular basis of the high-affinity activation of type 1 ryanodine receptors by imperatoxin A","volume":"377","author":"Lee","year":"2004","journal-title":"Biochem. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0014-5793(00)01239-4","article-title":"Chemical synthesis and characterization of maurocalcine, a scorpion toxin that activates Ca(2+) release channel\/ryanodine receptors","volume":"469","author":"Fajloun","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/1097-0134(20000815)40:3<436::AID-PROT90>3.0.CO;2-9","article-title":"A new fold in the scorpion toxin family, associated with an activity on a ryanodine-sensitive calcium channel","volume":"40","author":"Mosbah","year":"2000","journal-title":"Proteins"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/jbt.20382","article-title":"ImKTx1, a new Kv1.3 channel blocker with a unique primary structure","volume":"25","author":"Chen","year":"2010","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.peptides.2005.10.010","article-title":"Cloning and characterization of a novel calcium channel toxin-like gene BmCa1 from Chinese scorpion Mesobuthus martensii Karsch","volume":"27","author":"Zhijian","year":"2006","journal-title":"Peptides"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.toxicon.2007.06.014","article-title":"Purification and characterization of a novel short-chain insecticidal toxin with two disulfide bridges from the venom of the scorpion Liocheles australasiae","volume":"50","author":"Matsushita","year":"2007","journal-title":"Toxicon"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"10478","DOI":"10.1073\/pnas.1103501108","article-title":"Unique scorpion toxin with a putative ancestral fold provides insight into evolution of the inhibitor cystine knot motif","volume":"108","author":"Smith","year":"2011","journal-title":"Proc. Natl. Acad. Sci.USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8906","DOI":"10.1073\/pnas.1214062110","article-title":"Multiple actions of \u03c6-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins","volume":"110","author":"Smith","year":"2013","journal-title":"Proc. Natl. Acad. Sci.USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.bbrc.2011.07.016","article-title":"Solution structure of a short-chain insecticidal toxin LaIT1 from the venom of scorpion Liocheles australasiae","volume":"411","author":"Horita","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8397","DOI":"10.1016\/S0021-9258(18)34345-X","article-title":"Insect toxic component from the venom of a chactoid scorpion, Scorpio maurus palmatus (Scorpionidae)","volume":"257","author":"Lazarovici","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.toxicon.2012.11.017","article-title":"Characterization of the venom from the Australian scorpion Urodacus yaschenkoi: Molecular mass analysis of components, cDNA sequences and peptides with antimicrobial activity","volume":"63","author":"Batista","year":"2013","journal-title":"Toxicon"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0041-0101(03)00236-8","article-title":"New insight on scorpion divergence inferred from comparative analysis of toxin structure, pharmacology and distribution","volume":"42","author":"Froy","year":"2003","journal-title":"Toxicon"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5369","DOI":"10.1046\/j.1432-1033.2002.03171.x","article-title":"A single charged surface residue modifies the activity of ikitoxin, a beta-type Na+ channel toxin from Parabuthus transvaalicus","volume":"269","author":"Inceoglu","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.toxicon.2006.09.023","article-title":"Voltage-gated sodium channel modulation by scorpion alpha-toxins","volume":"49","author":"Bosmans","year":"2007","journal-title":"Toxicon"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jprot.2013.06.007","article-title":"Molecular diversity of Chaerilidae venom peptides reveals the dynamic evolution of scorpion venom components from Buthidae to non-Buthidae","volume":"89C","author":"He","year":"2013","journal-title":"J. Proteomics"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bbapap.2004.09.020","article-title":"Isolation and molecular characterization of LVP1 lipolysis activating peptide from scorpion Buthus occitanus tunetanus","volume":"1747","author":"Soudani","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/75921","article-title":"Discovery and characterization of a family of insecticidal neurotoxins with a rare vicinal disulfide bridge","volume":"7","author":"Wang","year":"2000","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/molbev\/msp251","article-title":"Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma)","volume":"27","author":"Fry","year":"2010","journal-title":"Mol. Biol. Evol."},{"key":"ref_75","first-page":"247","article-title":"A novel class of pore-forming peptides in the venom of parabuthus schlechteri Purcell (scorpions: buthidae)","volume":"16","author":"Verdonck","year":"2000","journal-title":"Cimbebasia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4799","DOI":"10.1046\/j.1432-1033.2002.03177.x","article-title":"Antibacterial and antifungal properties of \u03b1-helical, cationic peptides in the venom of scorpions from southern Africa","volume":"269","author":"Moerman","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1016\/S0041-0101(02)00183-6","article-title":"Cationic peptides from scorpion venom can stimulate and inhibit polymorphonuclear granulocytes","volume":"40","author":"Willems","year":"2002","journal-title":"Toxicon"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.bbrc.2003.09.175","article-title":"Antimicrobial peptides from scorpion venom induce Ca(2+) signaling in HL-60 cells","volume":"311","author":"Moerman","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.peptides.2004.04.008","article-title":"Parabutoporin--an antibiotic peptide from scorpion venom--can both induce activation and inhibition of granulocyte cell functions","volume":"25","author":"Willems","year":"2004","journal-title":"Peptides"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Roelants, K., Fry, B.G., Ye, L., Norman, J.A., Stijlemans, B., Kok, P., Clynen, E., Schoofs, L., Cornelis, P., and Bossuyt, F. (2013). Evolutionary genomics of an amphibian defense peptide arsenal. PLoS Genet., in press.","DOI":"10.1371\/journal.pgen.1003662"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e81827","DOI":"10.1371\/journal.pone.0081827","article-title":"Molecular evolution of vertebrate neurotrophins: Co-option of the highly conserved nerve growth factor gene into the advanced snake venom arsenal","volume":"8","author":"Sunagar","year":"2013","journal-title":"PLoS One"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1023\/A:1020651607164","article-title":"Snake venom hyaluronidase: an evidence for isoforms and extracellular matrix degradation","volume":"240","author":"Girish","year":"2002","journal-title":"Mol Cell Biochem"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/molbev\/msm088","article-title":"PAML 4: Phylogenetic analysis by maximum likelihood","volume":"24","author":"Yang","year":"2007","journal-title":"Mol. Biol. Evol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/PL00006320","article-title":"Synonymous and nonsynonymous rate variation in nuclear genes of mammals","volume":"46","author":"Yang","year":"1998","journal-title":"J. Mol. Evol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1093\/oxfordjournals.molbev.a004152","article-title":"Accuracy and power of Bayes prediction of amino acid sites under positive selection","volume":"19","author":"Anisimova","year":"2002","journal-title":"Mol. Biol. Evol."},{"key":"ref_86","first-page":"200","article-title":"ADOPS--Automatic Detection Of Positively Selected Sites","volume":"9","author":"Vieira","year":"2012","journal-title":"J. Integr. Bioinform."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e1002764","DOI":"10.1371\/journal.pgen.1002764","article-title":"Detecting individual sites subject to episodic diversifying selection","volume":"8","author":"Murrell","year":"2012","journal-title":"PLoS Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1093\/molbev\/mst030","article-title":"FUBAR: a fast, unconstrained bayesian approximation for inferring selection","volume":"30","author":"Murrell","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1093\/molbev\/msi105","article-title":"Not so different after all: a comparison of methods for detecting amino acid sites under selection","volume":"22","author":"Frost","year":"2005","journal-title":"Mol. Biol. Evol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/bioinformatics\/btg043","article-title":"TreeSAAP: selection on amino acid properties using phylogenetic trees","volume":"19","author":"Woolley","year":"2003","journal-title":"Bioinformatics"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1093\/molbev\/msr125","article-title":"A random effects branch-site model for detecting episodic diversifying selection","volume":"28","author":"Murrell","year":"2011","journal-title":"Mol. Biol. Evol."},{"key":"ref_92","first-page":"7","article-title":"Mass landscapes of seven scorpion species: The first analyses of Australian species with 1,5-DAN matrix","volume":"3","author":"Smith","year":"2012","journal-title":"J. Venom Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"13813","DOI":"10.1074\/jbc.M112.343996","article-title":"Hg1, novel peptide inhibitor specific for Kv1.3 channels from first scorpion Kunitz-type potassium channel toxin family","volume":"287","author":"Chen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/PL00006450","article-title":"Accelerated evolution and molecular surface of venom phospholipase A2 enzymes","volume":"48","author":"Kini","year":"1999","journal-title":"J. Mol. Evol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s00239-013-9552-5","article-title":"Molecular phylogeny and evolution of the proteins encoded by coleoid (cuttlefish, octopus, and squid) posterior venom glands","volume":"76","author":"Ruder","year":"2013","journal-title":"J. Mol. Evol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.3390\/toxins5112172","article-title":"Three-Fingered RAVERs: Rapid Accumulation of Variations in Exposed Residues of Snake Venom Toxins","volume":"5","author":"Sunagar","year":"2013","journal-title":"Toxins"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1096\/fj.11-187179","article-title":"Molding the business end of neurotoxins by diversifying evolution","volume":"26","author":"Zilberberg","year":"2012","journal-title":"FASEB J."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.toxicon.2007.11.010","article-title":"Positively selected sites of scorpion depressant toxins: possible roles in toxin functional divergence","volume":"51","author":"Tian","year":"2008","journal-title":"Toxicon"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s00239-003-2534-2","article-title":"Adaptive evolution of scorpion sodium channel toxins","volume":"58","author":"Zhu","year":"2004","journal-title":"J. Mol. Evol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.toxicon.2012.04.343","article-title":"Investigating the chemical profile of regenerated scorpion (Parabuthus transvaalicus) venom in relation to metabolic cost and toxicity","volume":"60","author":"Nisani","year":"2012","journal-title":"Toxicon"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1644\/07-MAMM-A-374.1","article-title":"Acquired resistance to saliva anticoagulants by prey previously fed upon by vampire bats (Desmodus rotundus): Evidence for immune response","volume":"90","author":"Delpietro","year":"2009","journal-title":"J. Mamm."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3420","DOI":"10.1093\/nar\/gkn176","article-title":"High-throughput functional annotation and data mining with the Blast2GO suite","volume":"36","author":"Gotz","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/bioinformatics\/btr059","article-title":"B2G-FAR, a species-centered GO annotation repository","volume":"27","author":"Gotz","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_104","unstructured":"Chairman, V., and Kusk, K. (2011). CLC Main Workbench, CLC bio. version 6.7.1."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/sysbio\/sys029","article-title":"MrBayes 3.2: efficient Bayesian phylogenetic inference and model choice across a large model space","volume":"61","author":"Ronquist","year":"2012","journal-title":"Syst. Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/sysbio\/syq010","article-title":"New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0","volume":"59","author":"Guindon","year":"2010","journal-title":"Syst. Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1093\/molbev\/msl051","article-title":"Automated phylogenetic detection of recombination using a genetic algorithm","volume":"23","author":"Posada","year":"2006","journal-title":"Mol. Biol. Evol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1093\/bioinformatics\/btl427","article-title":"Robust inference of positive selection from recombining coding sequences","volume":"22","author":"Scheffler","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_109","first-page":"725","article-title":"A codon-based model of nucleotide substitution for protein-coding DNA sequences","volume":"11","author":"Goldman","year":"1994","journal-title":"Mol. Biol. Evol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1093\/oxfordjournals.molbev.a025957","article-title":"Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution","volume":"15","author":"Yang","year":"1998","journal-title":"Mol. Biol. Evol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1093\/genetics\/148.3.929","article-title":"Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene","volume":"148","author":"Nielsen","year":"1998","journal-title":"Genetics"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1093\/molbev\/msi097","article-title":"Bayes empirical Bayes inference of amino acid sites under positive selection","volume":"22","author":"Yang","year":"2005","journal-title":"Mol. Biol. Evol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1093\/bioinformatics\/bti079","article-title":"V HyPhy: hypothesis testing using phylogenies","volume":"21","author":"Pond","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/molbev\/msp260","article-title":"Evolutionary fingerprinting of genes","volume":"27","author":"Pond","year":"2010","journal-title":"Mol. Biol. Evol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nprot.2009.2","article-title":"Protein structure prediction on the Web: a case study using the Phyre server","volume":"4","author":"Kelley","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_116","unstructured":"DeLano, W.L. (2002). The PyMOL Molecular Graphics System, Schr\u00f6dinger, LLC. version 1.5."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1006\/jmbi.2000.4474","article-title":"ConSurf: an algorithmic tool for the identification of functional regions in proteins by surface mapping of phylogenetic information","volume":"307","author":"Armon","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/(SICI)1096-987X(199802)19:3<319::AID-JCC6>3.0.CO;2-W","article-title":"Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules","volume":"19","author":"Fraczkiewicz","year":"1998","journal-title":"J. Comput. Chem."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/5\/12\/2456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:51:22Z","timestamp":1760219482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/5\/12\/2456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,13]]},"references-count":118,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2013,12]]}},"alternative-id":["toxins5122456"],"URL":"https:\/\/doi.org\/10.3390\/toxins5122456","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,13]]}}}