title: kappa-Hefutoxin1, a novel toxin from the scorpion Heterometrus fulvipes with unique structure and function. Importance of the functional diad in potassium channel selectivity.
abstract: An important and exciting challenge in the postgenomic era is to understand the functions of newly discovered proteins based on their structures. The main thrust is to find the common structural motifs that contribute to specific functions. Using this premise, here we report the purification, solution NMR, and functional characterization of a novel class of weak potassium channel toxins from the venom of the scorpion Heterometrus fulvipes. These toxins, kappa-hefutoxin1 and kappa-hefutoxin2, exhibit no homology to any known toxins. NMR studies indicate that kappa-hefutoxin1 adopts a unique three-dimensional fold of two parallel helices linked by two disulfide bridges without any beta-sheets. Based on the presence of the functional diad (Tyr(5)/Lys(19)) at a distance (6.0 +/- 1.0 A) comparable with other potassium channel toxins, we hypothesized its function as a potassium channel toxin. kappa-Hefutoxin 1 not only blocks the voltage-gated K(+)-channels, Kv1.3 and Kv1.2, but also slows the activation kinetics of Kv1.3 currents, a novel feature of kappa-hefutoxin 1, unlike other scorpion toxins, which are considered solely pore blockers. Alanine mutants (Y5A, K19A, and Y5A/K19A) failed to block the channels, indicating the importance of the functional diad.
authors.affiliation: Venom and Toxin Research Programme, Faculty of Medicine, National University of Singapore, 4 Medical Dr., Singapore 117597, Singapore.
authors.forename: Kellathur N
authors.initials: KN
authors.lastname: Srinivasan
authors.forename: Vaithiyalingam
authors.initials: V
authors.lastname: Sivaraja
authors.forename: Isabelle
authors.initials: I
authors.lastname: Huys
authors.forename: Toru
authors.initials: T
authors.lastname: Sasaki
authors.forename: Betty
authors.initials: B
authors.lastname: Cheng
authors.forename: Thallampuranam Krishnaswamy S
authors.initials: TK
authors.lastname: Kumar
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sato
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.forename: Chin
authors.initials: C
authors.lastname: Yu
authors.forename: B Chia Cheng
authors.initials: BC
authors.lastname: San
authors.forename: Shoba
authors.initials: S
authors.lastname: Ranganathan
authors.forename: H John
authors.initials: HJ
authors.lastname: Bowie
authors.forename: R Manjunatha
authors.initials: RM
authors.lastname: Kini
authors.forename: Ponnampalam
authors.initials: P
authors.lastname: Gopalakrishnakone
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D015221:Potassium Channels / Q000187:drug effects*; D011487:Protein Conformation; D012605:Scorpions; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D014118:Toxins, Biological / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
chemical_list: D015221:Potassium Channels; D014118:Toxins, Biological