Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 33, Pages 17049-17065Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.729095
Keywords
membrane bilayer; peptides; sodium channel; toxin; transmembrane domain; NaV1; 7; analgesic; gating modifier toxin; peptide-lipid interactions; voltage-gated ion channel
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Funding
- Australian National Health and Medical Research Center [APP1080405, APP1071293, APP1044414, APP1072113]
- Australian Research Council in the form of an Australian Research Council Discovery Outstanding Researcher Grant [DP130102153, FT130101215]
- Australian Research Council Australian Laureate Fellowship [FL150100146]
- Institute for Molecular Bioscience Industry Fellowship
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ProTx-II is a disulfide-rich peptide toxin from tarantula venom able to inhibit the human voltage-gated sodium channel 1.7 (hNa(V)1.7), 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 hNa(V)1.7, 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 hNa(V)1.7 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 hNa(V)1.7 channel inhibitor.
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