scholarly journals Helical Structure of the Cooh Terminus of S3 and Its Contribution to the Gating Modifier Toxin Receptor in Voltage-Gated Ion Channels

2001 ◽  
Vol 117 (3) ◽  
pp. 205-218 ◽  
Author(s):  
Yingying Li-Smerin ◽  
Kenton J. Swartz

The voltage-sensing domains in voltage-gated K+ channels each contain four transmembrane (TM) segments, termed S1 to S4. Previous scanning mutagenesis studies suggest that S1 and S2 are amphipathic membrane spanning α-helices that interface directly with the lipid membrane. In contrast, the secondary structure of and/or the environments surrounding S3 and S4 are more complex. For S3, although the NH2-terminal part displays significant helical character in both tryptophan- and alanine-scanning mutagenesis studies, the structure of the COOH-terminal portion of this TM is less clear. The COOH terminus of S3 is particularly interesting because this is where gating modifier toxins like Hanatoxin interact with different voltage-gated ion channels. To further examine the secondary structure of the COOH terminus of S3, we lysine-scanned this region in the drk1 K+ channel and examined the mutation-induced changes in channel gating and Hanatoxin binding affinity, looking for periodicity characteristic of an α-helix. Both the mutation-induced perturbation in the toxin–channel interaction and in gating support the presence of an α-helix of at least 10 residues in length in the COOH terminus of S3. Together with previous scanning mutagenesis studies, these results suggest that, in voltage-gated K+ channels, the entire S3 segment is helical, but that it can be divided into two parts. The NH2-terminal part of S3 interfaces with both lipid and protein, whereas the COOH-terminal part interfaces with water (where Hanatoxin binds) and possibly protein. A conserved proline residue is located near the boundary between the two parts of S3, arguing for the presence of a kink in this region. Several lines of evidence suggest that these structural features of S3 probably exist in all voltage-gated ion channels.

2000 ◽  
Vol 116 (5) ◽  
pp. 637-644 ◽  
Author(s):  
Jeffrey R. Winterfield ◽  
Kenton J. Swartz

The gating modifier toxins are a large family of protein toxins that modify either activation or inactivation of voltage-gated ion channels. ω-Aga-IVA is a gating modifier toxin from spider venom that inhibits voltage-gated Ca2+ channels by shifting activation to more depolarized voltages. We identified two Glu residues near the COOH-terminal edge of S3 in the α1A Ca2+ channel (one in repeat I and the other in repeat IV) that align with Glu residues previously implicated in forming the binding sites for gating modifier toxins on K+ and Na+ channels. We found that mutation of the Glu residue in repeat I of the Ca2+ channel had no significant effect on inhibition by ω-Aga-IVA, whereas the equivalent mutation of the Glu in repeat IV disrupted inhibition by the toxin. These results suggest that the COOH-terminal end of S3 within repeat IV contributes to forming a receptor for ω-Aga-IVA. The strong predictive value of previous mapping studies for K+ and Na+ channel toxins argues for a conserved binding motif for gating modifier toxins within the voltage-sensing domains of voltage-gated ion channels.


Toxicon ◽  
2007 ◽  
Vol 49 (2) ◽  
pp. 124-141 ◽  
Author(s):  
William A. Catterall ◽  
Sandrine Cestèle ◽  
Vladimir Yarov-Yarovoy ◽  
Frank H. Yu ◽  
Keiichi Konoki ◽  
...  

2007 ◽  
Vol 2 (3) ◽  
pp. 189-202 ◽  
Author(s):  
Le Jean-Yves ◽  
Ouadid-Ahidouch Halima ◽  
Soriani Olivier ◽  
Besson Pierre ◽  
Ahidouch Ahmed ◽  
...  

2009 ◽  
Vol 96 (3) ◽  
pp. 261a
Author(s):  
Muugu V. Brahmajothi ◽  
Michael. J. Morales ◽  
Donald L. Campbell ◽  
Charles Steenbergen ◽  
Harold C. Strauss

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