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κ-Hefutoxin1, a Novel Toxin from the ScorpionHeterometrus fulvipes with Unique Structure and Function

2002; Elsevier BV; Volume: 277; Issue: 33 Linguagem: Inglês

10.1074/jbc.m111258200

1083-351X

Kellathur N. Srinivasan, Sivaraja Vaithiyalingam, Isabelle Huys, Toru Sasaki, Betty Yee Man Cheng, Thallapuranam Krishnaswamy Suresh Kumar, Kazuki Sato, Jan Tytgat, Chin‐Hui Yu, B. Chia Cheng San, Shoba Ranganathan, H. John Bowie, R. Manjunatha Kini, P. Gopalakrishnakone,

Nicotinic Acetylcholine Receptors Study

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, κ-hefutoxin1 and κ-hefutoxin2, exhibit no homology to any known toxins. NMR studies indicate that κ-hefutoxin1 adopts a unique three-dimensional fold of two parallel helices linked by two disulfide bridges without any β−sheets. Based on the presence of the functional diad (Tyr 5 /Lys 19 ) at a distance (6.0 ± 1.0 Å) comparable with other potassium channel toxins, we hypothesized its function as a potassium channel toxin. κ-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 κ-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.