Interaction of tarantula venom peptide ProTx-II with lipid membranes is a prerequisite for its inhibition of human voltage-gated sodium channel NaV1.7

Troeira Henriques, Sonia, Deplazes, Evelyne, Lawrence, Nicole, Cheneval, Olivier, Chaousis, Stephanie, Inserra, Marco, Thongyoo, Panumart, King, Glenn F., Mark, Alan E., Vetter, Irina, Craik, David J. and Schroeder, Christina Ingrid (2016) Interaction of tarantula venom peptide ProTx-II with lipid membranes is a prerequisite for its inhibition of human voltage-gated sodium channel NaV1.7. The Journal of Biological Chemistry, 291 33: 17049-17065. doi:10.1074/jbc.M116.729095

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Author Troeira Henriques, Sonia
Deplazes, Evelyne
Lawrence, Nicole
Cheneval, Olivier
Chaousis, Stephanie
Inserra, Marco
Thongyoo, Panumart
King, Glenn F.
Mark, Alan E.
Vetter, Irina
Craik, David J.
Schroeder, Christina Ingrid
Title Interaction of tarantula venom peptide ProTx-II with lipid membranes is a prerequisite for its inhibition of human voltage-gated sodium channel NaV1.7
Formatted title
Interaction of tarantula venom peptide ProTx-II with lipid membranes is a prerequisite for its inhibition of human voltage-gated sodium channel NaV1.7
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2016-08-12
Sub-type Article (original research)
DOI 10.1074/jbc.M116.729095
Open Access Status File (Publisher version)
Volume 291
Issue 33
Start page 17049
End page 17065
Total pages 17
Place of publication Rockville, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
ProTx-II is a disulfide-rich peptide toxin from tarantula venom able to inhibit the human voltage-gated sodium channel 1.7 (hNaV1.7), a channel reported to be involved in nociception, and thus it might have potential as a pain therapeutic. ProTx-II acts by binding to the membrane-embedded voltage sensor domain of hNaV1.7, but the precise peptide channel-binding site and the importance of membrane binding on the inhibitory activity of ProTx-II remain unknown. In this study, we examined the structure and membrane-binding properties of ProTx-II and several analogues using NMR spectroscopy, surface plasmon resonance, fluorescence spectroscopy, and molecular dynamics simulations. Our results show a direct correlation between ProTx-II membrane binding affinity and its potency as an hNaV1.7 channel inhibitor. The data support a model whereby a hydrophobic patch on the ProTx-II surface anchors the molecule at the cell surface in a position that optimizes interaction of the peptide with the binding site on the voltage sensor domain. This is the first study to demonstrate that binding of ProTx-II to the lipid membrane is directly linked to its potency as an hNaV1.7 channel inhibitor.
Keyword Membrane bilayer
Peptides
Sodium channel
Toxin
Transmembrane domain
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Wed, 07 Sep 2016, 22:55:48 EST by Susan Allen on behalf of Institute for Molecular Bioscience