依赖于电压的离子通道响应于膜电压的变化而打开,但发生这一过程的分子机制却不清楚。由MacKinnon及其同事在2003年所做的先驱性工作表明,该过程涉及一种类脂暴露的“桨”状结构的运动,但这种运动的性质仍然存在争议。在两篇互补性文章的第一篇中,Alabi等人通过证明这种“桨”状结构的功能在移植进关系较远的通道中时被忠实保留下来的事实,说明了这种结构特征的重要性。这项工作还强调了膜内这一结构的移动性。Long等人描述了被由类脂排列成的一个类似于双层的体系所包围的一个被改变了的Kv1.2钾通道的高分辨率结构。“桨”状结构中的临界正电荷被类脂和蛋白相互作用所稳定,这说明了该“桨”状结构可能会以某种方式响应于电压的变化而运动,将该通道孔打开。(科学网)
原始出处:
Nature 450, 370-375 (15 November 2007) | doi:10.1038/nature06266; Received 31 July 2007; Accepted 17 September 2007
Portability of paddle motif function and pharmacology in voltage sensors
AbdulRasheed A. Alabi1,3, Maria Isabel Bahamonde1,3, Hoi Jong Jung2, Jae Il Kim2 & Kenton J. Swartz1
Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
Department of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 500-712, Korea
These authors contributed equally to this work.
Correspondence to: Kenton J. Swartz1 Correspondence and requests for materials should be addressed to K.J.S. (Email: swartzk@ninds.nih.gov).
Voltage-sensing domains enable membrane proteins to sense and react to changes in membrane voltage. Although identifiable S1–S4 voltage-sensing domains are found in an array of conventional ion channels and in other membrane proteins that lack pore domains, the extent to which their voltage-sensing mechanisms are conserved is unknown. Here we show that the voltage-sensor paddle, a motif composed of S3b and S4 helices, can drive channel opening with membrane depolarization when transplanted from an archaebacterial voltage-activated potassium channel (KvAP) or voltage-sensing domain proteins (Hv1 and Ci-VSP) into eukaryotic voltage-activated potassium channels. Tarantula toxins that partition into membranes can interact with these paddle motifs at the protein–lipid interface and similarly perturb voltage-sensor activation in both ion channels and proteins with a voltage-sensing domain. Our results show that paddle motifs are modular, that their functions are conserved in voltage sensors, and that they move in the relatively unconstrained environment of the lipid membrane. The widespread targeting of voltage-sensor paddles by toxins demonstrates that this modular structural motif is an important pharmacological target.