Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel NaV1.7.

Henriques, ST; Deplazes, E; Lawrence, N; Cheneval, O; Chaousis, S; Inserra, M; Thongyoo, P; King, GF; Mark, AE; Vetter, I; Craik, DJ; Schroeder, CI

Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel NaV1.7.

Henriques, ST Deplazes, E

Lawrence, N Cheneval, O Chaousis, S Inserra, M Thongyoo, P King, GF Mark, AE Vetter, I Craik, DJ Schroeder, CI

Permalink

Publisher:: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Publication Type:: Journal Article
Citation:: J Biol Chem, 2016, 291, (33), pp. 17049-17065
Issue Date:: 2016-08-12

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download full textAdobe PDF (3.44 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Henriques, ST
dc.contributor.author	Deplazes, E https://orcid.org/0000-0003-2052-5536
dc.contributor.author	Lawrence, N
dc.contributor.author	Cheneval, O
dc.contributor.author	Chaousis, S
dc.contributor.author	Inserra, M
dc.contributor.author	Thongyoo, P
dc.contributor.author	King, GF
dc.contributor.author	Mark, AE
dc.contributor.author	Vetter, I
dc.contributor.author	Craik, DJ
dc.contributor.author	Schroeder, CI
dc.date.accessioned	2022-03-24T05:32:56Z
dc.date.available	2022-03-24T05:32:56Z
dc.date.issued	2016-08-12
dc.identifier.citation	J Biol Chem, 2016, 291, (33), pp. 17049-17065
dc.identifier.issn	0021-9258
dc.identifier.issn	1083-351X
dc.identifier.uri	http://hdl.handle.net/10453/155517
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.relation.ispartof	J Biol Chem
dc.relation.isbasedon	10.1074/jbc.M116.729095
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.mesh	Binding Sites
dc.subject.mesh	Humans
dc.subject.mesh	Lipid Bilayers
dc.subject.mesh	Molecular Dynamics Simulation
dc.subject.mesh	NAV1.7 Voltage-Gated Sodium Channel
dc.subject.mesh	Nuclear Magnetic Resonance, Biomolecular
dc.subject.mesh	Spider Venoms
dc.subject.mesh	Humans
dc.subject.mesh	Lipid Bilayers
dc.subject.mesh	Spider Venoms
dc.subject.mesh	Nuclear Magnetic Resonance, Biomolecular
dc.subject.mesh	Binding Sites
dc.subject.mesh	Molecular Dynamics Simulation
dc.subject.mesh	NAV1.7 Voltage-Gated Sodium Channel
dc.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.
dc.type	Journal Article
utslib.citation.volume	291
utslib.location.activity	United States
utslib.for	03 Chemical Sciences
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.date.updated	2022-03-24T05:32:54Z
pubs.issue	33
pubs.publication-status	Published
pubs.volume	291
utslib.citation.issue	33

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/155517