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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>
Lee, Chul Won,Bae, Chanhyung,Lee, Jaeho,Ryu, Jae Ha,Kim, Ha Hyung,Kohno, Toshiyuki,Swartz, Kenton J.,Kim, Jae Il American Chemical Society 2012 Biochemistry Vol.51 No.9
<P/><P>Kurtoxin is a 63-amino acid polypeptide isolated from the venom of the South African scorpion <I>Parabuthus transvaalicus</I>. It is the first and only peptide ligand known to interact with Cav3 (T-type) voltage-gated Ca<SUP>2+</SUP> channels with high affinity and to modify the voltage-dependent gating of these channels. Here we describe the nuclear magnetic resonance (NMR) solution structure of kurtoxin determined using two- and three-dimensional NMR spectroscopy with dynamical simulated annealing calculations. The molecular structure of the toxin was highly similar to those of scorpion α-toxins and contained an α-helix, three β-strands, and several turns stabilized by four disulfide bonds. This so-called “cysteine-stabilized α-helix and β-sheet (CSαβ)” motif is found in a number of functionally varied small proteins. A detailed comparison of the backbone structure of kurtoxin with those of the scorpion α-toxins revealed that three regions [first long loop (Asp<SUP>8</SUP>–Ile<SUP>15</SUP>), β-hairpin loop (Gly<SUP>39</SUP>–Leu<SUP>42</SUP>), and C-terminal segment (Arg<SUP>57</SUP>–Ala<SUP>63</SUP>)] in kurtoxin significantly differ from the corresponding regions in scorpion α-toxins, suggesting that these regions may be important for interacting with Cav3 (T-type) Ca<SUP>2+</SUP> channels. In addition, the surface profile of kurtoxin shows a larger and more focused electropositive patch along with a larger hydrophobic surface compared to those seen on scorpion α-toxins. These distinct surface properties of kurtoxin could explain its binding to Cav3 (T-type) voltage-gated Ca<SUP>2+</SUP> channels.</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>