Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel NaV1.7.
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.
From the Institute for Molecular Bioscience and s.henriques@uq.edu.au.
Sónia Troeira
ST
Henriques
From the Institute for Molecular Bioscience and School of Chemistry and Molecular Biosciences, University of Queensland, Queensland 4072 and.
Evelyne
E
Deplazes
From the Institute for Molecular Bioscience and.
Nicole
N
Lawrence
From the Institute for Molecular Bioscience and.
Olivier
O
Cheneval
From the Institute for Molecular Bioscience and.
Stephanie
S
Chaousis
From the Institute for Molecular Bioscience and.
Marco
M
Inserra
From the Institute for Molecular Bioscience and.
Panumart
P
Thongyoo
From the Institute for Molecular Bioscience and.
Glenn F
GF
King
From the Institute for Molecular Bioscience and School of Chemistry and Molecular Biosciences, University of Queensland, Queensland 4072 and.
Alan E
AE
Mark
From the Institute for Molecular Bioscience and the School of Pharmacy, University of Queensland, Queensland 4102, Australia.
Irina
I
Vetter
From the Institute for Molecular Bioscience and.
David J
DJ
Craik
From the Institute for Molecular Bioscience and c.schroeder@imb.uq.edu.au.
Christina I
CI
Schroeder
D001665:Binding Sites; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D013111:Spider Venoms / Q000737:chemistry*
D008051:Lipid Bilayers; D062556:NAV1.7 Voltage-Gated Sodium Channel; C470626:ProTx-II peptide; C486866:SCN9A protein, human; D013111:Spider Venoms
NaV1.7; analgesic; gating modifier toxin; membrane bilayer; peptide-lipid interactions; peptides; sodium channel; toxin; transmembrane domain; voltage-gated ion channel