Plectasin, first animal toxin-like fungal defensin blocking potassium channels through recognizing channel pore region.

Fang Xiang,Zhijian Cao,Wenxin Li,Jing Feng,Zili Xie,Yingliang Wu,Weishan Yang,Zongyun Chen

doi:10.3390/toxins7010034

Abstract

The potassium channels were recently found to be inhibited by animal toxin-like human β-defensin 2 (hBD2), the first defensin blocker of potassium channels. Whether there are other defensin blockers from different organisms remains an open question. Here, we reported the potassium channel-blocking plectasin, the first defensin blocker from a fungus. Based on the similar cysteine-stabilized alpha-beta (CSαβ) structure between plectasin and scorpion toxins acting on potassium channels, we found that plectasin could dose-dependently block Kv1.3 channel currents through electrophysiological experiments. Besides Kv1.3 channel, plectasin could less inhibit Kv1.1, Kv1.2, IKCa, SKCa3, hERG and KCNQ channels at the concentration of 1 μΜ. Using mutagenesis and channel activation experiments, we found that outer pore region of Kv1.3 channel was the binding site of plectasin, which is similar to the interacting site of Kv1.3 channel recognized by animal toxin blockers. Together, these findings not only highlight the novel function of plectasin as a potassium channel inhibitor, but also imply that defensins from different organisms functionally evolve to be a novel kind of potassium channel inhibitors.

Highlights

Mammalian potassium channels are a diverse and ubiquitous family of membrane proteins responsible for the physiological and pathological activities in both excitable and nonexcitable cells [1].These functional roles have been well elucidated by numerous toxin peptides from venomous animals, such as scorpion, snake, sea anemone, cone snail and bee [2,3,4,5]
These toxins showed high potency and selectivity towards potassium channels with physically blocking the channel pore region explored by docking and molecular dynamic simulations, such as Kv1.3 channel-blocking sea anemone toxin ShK
Plectasin shows less similar primary structure to those of scorpion toxins acting on potassium channels (Figure 1A), it forms scorpion toxin-like CSαβ structure stabilized by three disulfide bonds (Figure 1B–E)

Summary

Introduction

Mammalian potassium channels are a diverse and ubiquitous family of membrane proteins responsible for the physiological and pathological activities in both excitable and nonexcitable cells [1] These functional roles have been well elucidated by numerous toxin peptides from venomous animals, such as scorpion, snake, sea anemone, cone snail and bee [2,3,4,5]. These toxins showed high potency and selectivity towards potassium channels with physically blocking the channel pore region explored by docking and molecular dynamic simulations, such as Kv1.3 channel-blocking sea anemone toxin ShK analogues and scorpion toxin HsTx1 analogues [6,7,8,9]. Such progress is initiating the discovery process of various defensins as potassium channel blockers from different organisms

Methods

Results

Conclusion