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Mapping the interaction surface of scorpion β-toxins with an insect sodium channel.

Publication ,  Journal Article
Zhorov, BS; Du, Y; Song, W; Luo, N; Gordon, D; Gurevitz, M; Dong, K
Published in: The Biochemical journal
July 2021

The interaction of insect-selective scorpion depressant β-toxins (LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus) with the Blattella germanica sodium channel, BgNav1-1a, was investigated using site-directed mutagenesis, electrophysiological analyses, and structural modeling. Focusing on the pharmacologically defined binding site-4 of scorpion β-toxins at the voltage-sensing domain II (VSD-II), we found that charge neutralization of D802 in VSD-II greatly enhanced the channel sensitivity to Lqh-dprIT3. This was consistent with the high sensitivity of the splice variant BgNav2-1, bearing G802, to Lqh-dprIT3, and low sensitivity of BgNav2-1 mutant, G802D, to the toxin. Further mutational and electrophysiological analyses revealed that the sensitivity of the WT = D802E < D802G < D802A < D802K channel mutants to Lqh-dprIT3 correlated with the depolarizing shifts of activation in toxin-free channels. However, the sensitivity of single mutants involving IIS4 basic residues (K4E = WT << R1E < R2E < R3E) or double mutants (D802K = K4E/D802K = R3E/D802K > R2E/D802K > R1E/D802K > WT) did not correlate with the activation shifts. Using the cryo-EM structure of the Periplaneta americana channel, NavPaS, as a template and the crystal structure of LqhIT2, we constructed structural models of LqhIT2 and Lqh-dprIT3-c in complex with BgNav1-1a. These models along with the mutational analysis suggest that depressant toxins approach the salt-bridge between R1 and D802 at VSD-II to form contacts with linkers IIS1-S2, IIS3-S4, IIIP5-P1 and IIIP2-S6. Elimination of this salt-bridge enables deeper penetration of the toxin into a VSD-II gorge to form new contacts with the channel, leading to increased channel sensitivity to Lqh-dprIT3.

Duke Scholars

Published In

The Biochemical journal

DOI

EISSN

1470-8728

ISSN

0264-6021

Publication Date

July 2021

Volume

478

Issue

14

Start / End Page

2843 / 2869

Related Subject Headings

  • Xenopus
  • Sodium Channels
  • Scorpions
  • Scorpion Venoms
  • Protein Interaction Mapping
  • Protein Domains
  • Protein Binding
  • Patch-Clamp Techniques
  • Oocytes
  • Neoptera
 

Citation

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MLA
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Zhorov, B. S., Du, Y., Song, W., Luo, N., Gordon, D., Gurevitz, M., & Dong, K. (2021). Mapping the interaction surface of scorpion β-toxins with an insect sodium channel. The Biochemical Journal, 478(14), 2843–2869. https://doi.org/10.1042/bcj20210336
Zhorov, Boris S., Yuzhe Du, Weizhong Song, Ningguang Luo, Dalia Gordon, Michael Gurevitz, and Ke Dong. “Mapping the interaction surface of scorpion β-toxins with an insect sodium channel.The Biochemical Journal 478, no. 14 (July 2021): 2843–69. https://doi.org/10.1042/bcj20210336.
Zhorov BS, Du Y, Song W, Luo N, Gordon D, Gurevitz M, et al. Mapping the interaction surface of scorpion β-toxins with an insect sodium channel. The Biochemical journal. 2021 Jul;478(14):2843–69.
Zhorov, Boris S., et al. “Mapping the interaction surface of scorpion β-toxins with an insect sodium channel.The Biochemical Journal, vol. 478, no. 14, July 2021, pp. 2843–69. Epmc, doi:10.1042/bcj20210336.
Zhorov BS, Du Y, Song W, Luo N, Gordon D, Gurevitz M, Dong K. Mapping the interaction surface of scorpion β-toxins with an insect sodium channel. The Biochemical journal. 2021 Jul;478(14):2843–2869.

Published In

The Biochemical journal

DOI

EISSN

1470-8728

ISSN

0264-6021

Publication Date

July 2021

Volume

478

Issue

14

Start / End Page

2843 / 2869

Related Subject Headings

  • Xenopus
  • Sodium Channels
  • Scorpions
  • Scorpion Venoms
  • Protein Interaction Mapping
  • Protein Domains
  • Protein Binding
  • Patch-Clamp Techniques
  • Oocytes
  • Neoptera