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Tarantula Toxins Interact with Voltage Sensors within Lipid Membranes
Milescu, Mirela,Vobecky, Jan,Roh, Soung H.,Kim, Sung H.,Jung, Hoi J.,Kim, Jae Il,Swartz, Kenton J. Rockefeller University Press 2007 The Journal of general physiology Vol.130 No.5
<P>Voltage-activated ion channels are essential for electrical signaling, yet the mechanism of voltage sensing remains under intense investigation. The voltage-sensor paddle is a crucial structural motif in voltage-activated potassium (K<SUB>v</SUB>) channels that has been proposed to move at the protein–lipid interface in response to changes in membrane voltage. Here we explore whether tarantula toxins like hanatoxin and SGTx1 inhibit K<SUB>v</SUB> channels by interacting with paddle motifs within the membrane. We find that these toxins can partition into membranes under physiologically relevant conditions, but that the toxin–membrane interaction is not sufficient to inhibit K<SUB>v</SUB> channels. From mutagenesis studies we identify regions of the toxin involved in binding to the paddle motif, and those important for interacting with membranes. Modification of membranes with sphingomyelinase D dramatically alters the stability of the toxin–channel complex, suggesting that tarantula toxins interact with paddle motifs within the membrane and that they are sensitive detectors of lipid–channel interactions.</P>
Structure and Orientation of a Voltage-Sensor Toxin in Lipid Membranes
Jung, Hyun Ho,Jung, Hoi Jong,Milescu, Mirela,Lee, Chul Won,Lee, Seungkyu,Lee, Ju Yeon,Eu, Young-Jae,Kim, Ha Hyung,Swartz, Kenton J.,Kim, Jae Il Elsevier 2010 Biophysical journal Vol.99 No.2
<P><B>Abstract</B></P><P>Amphipathic protein toxins from tarantula venom inhibit voltage-activated potassium (Kv) channels by binding to a critical helix-turn-helix motif termed the voltage sensor paddle. Although these toxins partition into membranes to bind the paddle motif, their structure and orientation within the membrane are unknown. We investigated the interaction of a tarantula toxin named SGTx with membranes using both fluorescence and NMR spectroscopy. Depth-dependent fluorescence-quenching experiments with brominated lipids suggest that Trp<SUP>30</SUP> in SGTx is positioned ∼9 Å from the center of the bilayer. NMR spectra reveal that the inhibitor cystine knot structure of the toxin does not radically change upon membrane partitioning. Transferred cross-saturation NMR experiments indicate that the toxin's hydrophobic protrusion contacts the hydrophobic core of the membrane, whereas most surrounding polar residues remain at interfacial regions of the bilayer. The inferred orientation of the toxin reveals a twofold symmetry in the arrangement of basic and hydrophobic residues, a feature that is conserved among tarantula toxins. These results have important implications for regions of the toxin involved in recognizing membranes and voltage-sensor paddles, and for the mechanisms by which tarantula toxins alter the activity of different types of ion channels.</P>