title: Evidence for domain-specific recognition of SK and Kv channels by MTX and HsTx1 scorpion toxins.
abstract: Maurotoxin (MTX) and HsTx1 are two scorpion toxins belonging to the alpha-KTx6 structural family. These 34-residue toxins, cross-linked by four disulfide bridges, share 59% sequence identity and fold along the classical alpha/beta scaffold. Despite these structural similarities, they fully differ in their pharmacological profiles. MTX is highly active on small (SK) and intermediate (IK) conductance Ca(2+)-activated (K(+)) channels and on voltage-gated Kv1.2 channel, whereas HsTx1 potently blocks voltage-gated Kv1.1 and Kv1.3 channels only. Here, we designed and chemically produced MTX-HsTx1, a chimera of both toxins that contains the N-terminal helical region of MTX (sequence 1-16) and the C-terminal beta-sheet region of HsTx1 (sequence 17-34). The three-dimensional structure of the peptide in solution was solved by (1)H NMR. MTX-HsTx1 displays the activity of MTX on SK channel, whereas it exhibits the pharmacological profile of HsTx1 on Kv1.1, Kv1.2, Kv1.3, and IK channels. These data demonstrate that the helical region of MTX exerts a key role in SK channel recognition, whereas the beta-sheet region of HsTx1 is crucial for activity on all other channel types tested.
authors.affiliation: CNRS Formation de Recherche Expérimentale 2738, Laboratoire de Biochimie, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France.
authors.forename: Imed
authors.initials: I
authors.lastname: Regaya
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.forename: Gilles
authors.initials: G
authors.lastname: Ferrat
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andreotti
authors.forename: Hervé
authors.initials: H
authors.lastname: Darbon
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sabatier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004220:Disulfides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D051662:Kv1.1 Potassium Channel; D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D024681:Potassium Channels, Calcium-Activated / Q000737:chemistry*; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry / Q000494:pharmacology*; D020539:Sequence Analysis, Protein; D051640:Small-Conductance Calcium-Activated Potassium Channels; D055672:Static Electricity; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors
chemical_list: D004220:Disulfides; C496947:Kcna1 protein, mouse; C496970:Kcna2 protein, mouse; C496972:Kcna2 protein, rat; C496974:Kcna3 protein, mouse; C496975:Kcna3 protein, rat; D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; D051640:Small-Conductance Calcium-Activated Potassium Channels; C109471:TX1 toxin, Heterometrus spinnifer; C104498:maurotoxin; D051662:Kv1.1 Potassium Channel