Mihailescu Mihaela, Krepkiy Dmitriy, Milescu Mirela, Gawrisch Klaus, Swartz Kenton J, White Stephen
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850; National Institute of Standards and Technology Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899;
Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5463-70. doi: 10.1073/pnas.1415324111. Epub 2014 Dec 1.
Protein toxins from tarantula venom alter the activity of diverse ion channel proteins, including voltage, stretch, and ligand-activated cation channels. Although tarantula toxins have been shown to partition into membranes, and the membrane is thought to play an important role in their activity, the structural interactions between these toxins and lipid membranes are poorly understood. Here, we use solid-state NMR and neutron diffraction to investigate the interactions between a voltage sensor toxin (VSTx1) and lipid membranes, with the goal of localizing the toxin in the membrane and determining its influence on membrane structure. Our results demonstrate that VSTx1 localizes to the headgroup region of lipid membranes and produces a thinning of the bilayer. The toxin orients such that many basic residues are in the aqueous phase, all three Trp residues adopt interfacial positions, and several hydrophobic residues are within the membrane interior. One remarkable feature of this preferred orientation is that the surface of the toxin that mediates binding to voltage sensors is ideally positioned within the lipid bilayer to favor complex formation between the toxin and the voltage sensor.
狼蛛毒液中的蛋白质毒素会改变多种离子通道蛋白的活性，包括电压门控、牵张激活和配体激活的阳离子通道。尽管已证明狼蛛毒素可分配到膜中，并且认为膜在其活性中起重要作用，但这些毒素与脂质膜之间的结构相互作用却知之甚少。在此，我们使用固态核磁共振和中子衍射来研究电压传感器毒素（VSTx1）与脂质膜之间的相互作用，目的是确定毒素在膜中的定位并确定其对膜结构的影响。我们的结果表明，VSTx1定位于脂质膜的头部基团区域，并导致双层变薄。毒素的取向使得许多碱性残基处于水相中，所有三个色氨酸残基都处于界面位置，并且几个疏水残基位于膜内部。这种优选取向的一个显著特征是，介导与电压传感器结合的毒素表面理想地位于脂质双层内，有利于毒素与电压传感器之间形成复合物。
