CONUS PEPTIDES AND K CHANNELS

在过去的十年中，K通道的巨大分子多样性已经变得明显，明确K通道的单个分子形式的功能显然将是一个巨大的挑战。 在上一个资助期，我们发现了不同芋螺肽家族的显着多样性，所有这些家族显然都针对K通道。值得注意的是，芋螺物种的每个进化枝似乎都招募了不同的芋螺肽家族来靶向K通道。 我们将系统地探索四个这样的K通道靶向芋螺肽家族，其特征在于非常不同的程度：kappaM-芋螺毒素，conkunitzins，kappaA-芋螺毒素和I-超家族肽。 在资助期的初始阶段，我们将首先关注kappaM-芋螺毒素和conkunitzins，因为这些肽的先前表征比其他组更具实质性。虽然在kappaA-芋螺毒素和I-超家族肽中有相当大的潜力，但在这些肽可以系统地表征之前，必须克服常规化学合成和折叠的重大障碍。在靶向K通道的芋螺肽的不同组中发现的不同结构框架的令人惊讶的多样性为将来关于多种多样的芋螺肽：K通道复合物的结构-功能工作提供了基础。

The vast molecular diversity of K channels has become apparent in the last decade, and it clearly will be an enormous challenge to define the functions of individual molecular forms of K channels. In the last grant period, we uncovered a remarkable diversity of different conopeptide families all apparently targeted to K channels. Remarkably, each clade of Conus species appears to have recruited a different Conus peptide family to target K channels. We will systematically explore four such K channel-targeted Conus peptide families that have been characterized to very different extents: the kappaM-conotoxins, the conkunitzins, the kappaA-conotoxins and the I-superfamily peptides. In the initial phases of the grant period, we will focus first on the kappaM-conotoxins and conkunitzins since the previous characterization of these peptides has been more substantive than for the other groups. Although there is considerable potential in the kappaA-conotoxins and I-superfamily peptides, significant barriers to routine chemical synthesis and folding have to be overcome before these peptides can be systematically characterized. The surprising diversity of the different structural frameworks found in the divergent groups of Conus peptides that target K channels provides the foundation for future structure-function work on a wide diversity of conopeptide:K channel complexes.