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Studies of voltage-gated potassium (Kv) channels have identified the S3b\u2013S4 \u201cpaddle motif,\u201d which moves at the protein-lipid interface to drive channel opening, as the target for these amphipathic neurotoxins. Voltage-gated calcium (Cav) channels contain four homologous voltage sensor domains, suggesting multiple toxin binding sites. We show here that the S3\u2013S4 segments within Cav3.1 can be transplanted into Kv2.1 to examine their individual contributions to voltage sensing and pharmacology. With these results, we now have a more complete picture of the conserved nature of the paddle motif in all three major voltage-gated ion channel types (Kv, Nav and Cav). When screened with tarantula toxins, the four paddle sequences display distinct toxin binding properties, demonstrating that gating-modifier toxins can bind to Cav channels in a domain specific fashion. Domain III was the most commonly and strongly targeted and mutagenesis revealed an acidic residue that is important for toxin binding. We also measured the lipid partitioning strength of all toxins tested and observed a positive correlation with their inhibition of Cav3.1, suggesting a key role for membrane partitioning.<\/jats:p>","DOI":"10.1038\/srep23894","type":"journal-article","created":{"date-parts":[[2016,4,5]],"date-time":"2016-04-05T09:03:42Z","timestamp":1459847022000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Molecular Interactions between Tarantula Toxins and Low-Voltage-Activated Calcium Channels"],"prefix":"10.1038","volume":"6","author":[{"given":"Autoosa","family":"Salari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin S.","family":"Vega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorin S.","family":"Milescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirela","family":"Milescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,5]]},"reference":[{"key":"BFsrep23894_CR1","doi-asserted-by":"publisher","first-page":"a003947","DOI":"10.1101\/cshperspect.a003947","volume":"3","author":"WA Catterall","year":"2011","unstructured":"Catterall, W. 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