Molecular basis of the interaction between gating modifier spider toxins and the voltage sensor of voltage-gated ion channels.
Voltage-sensor domains (VSDs) are modular transmembrane domains of voltage-gated ion channels that respond to changes in membrane potential by undergoing conformational changes that are coupled to gating of the ion-conducting pore. Most spider-venom peptides function as gating modifiers by binding to the VSDs of voltage-gated channels and trapping them in a closed or open state. To understand the molecular basis underlying this mode of action, we used nuclear magnetic resonance to delineate the atomic details of the interaction between the VSD of the voltage-gated potassium channel KvAP and the spider-venom peptide VSTx1. Our data reveal that the toxin interacts with residues in an aqueous cleft formed between the extracellular S1-S2 and S3-S4 loops of the VSD whilst maintaining lipid interactions in the gaps formed between the S1-S4 and S2-S3 helices. The resulting network of interactions increases the energetic barrier to the conformational changes required for channel gating, and we propose that this is the mechanism by which gating modifier toxins inhibit voltage-gated ion channels.
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
Carus H Y
CHY
Lau
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
Glenn F
GF
King
Centre for Advanced Imaging, The University of Queensland, St. Lucia, QLD 4072, Australia.
Mehdi
M
Mobli
FEBS J. 2011 Mar;278(5):704-15
21214861
J Biomol NMR. 1995 Jul;6(1):1-10
22911575
Prog Nucl Magn Reson Spectrosc. 2013 Aug;73:1-16
23962882
J Am Chem Soc. 2010 Apr 28;132(16):5630-7
20356312
J Exp Biol. 2002 Mar;205(Pt 5):575-84
11907047
Methods Mol Biol. 2004;278:353-78
15318003
Nat Rev Drug Discov. 2006 Dec;5(12):993-6
17139284
Biochemistry. 2005 Apr 26;44(16):6015-23
15835890
Biochim Biophys Acta. 2016 Sep;1860(9):2053-63
27316322
J Med Chem. 2016 Mar 24;59(6):2704-17
26890998
J Biol Chem. 2008 Oct 3;283(40):27300-13
18628201
PLoS One. 2013 May 07;8(5):e63865
23667680
J Mol Biol. 2009 Jul 31;390(5):902-12
19481093
J Mol Biol. 2010 Nov 5;403(4):591-606
20851706
Neuron. 2010 Sep 23;67(6):915-28
20869590
Science. 2015 Dec 18;350(6267):aac5464
26680203
J Biol Chem. 2011 Aug 5;286(31):27301-10
21659528
Biochemistry. 2004 Aug 10;43(31):10071-9
15287735
Nature. 2004 Jul 8;430(6996):232-5
15241419
J Biol Chem. 2016 Jul 1;291(27):13974-86
27129258
Nature. 2011 Jul 10;475(7356):353-8
21743477
Acc Chem Res. 2014 Feb 18;47(2):708-17
24400700
Elife. 2015 May 07;4:e06774
25948544
J Biol Chem. 2013 Aug 2;288(31):22707-20
23760503
Biophys J. 2010 Jul 21;99(2):638-46
20643084
Sci Rep. 2015 Sep 18;5:14226
26382304
Mol Pharmacol. 2015 Dec;88(6):1002-10
26429937
Toxicon. 2007 Feb;49(2):124-41
17239913
J Magn Reson. 2010 May;204(1):160-4
20299257
Invert Neurosci. 2005 Nov;5(3-4):119-33
16172884
Nat Commun. 2014 Jul 11;5:4350
25014760
Nat Rev Drug Discov. 2003 Oct;2(10):790-802
14526382
Neuron. 1998 Oct;21(4):919-31
9808476
Expert Opin Biol Ther. 2011 Nov;11(11):1469-84
21939428
J Magn Reson. 2015 Jul;256:60-9
26004701
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15441-6
16223877
Nature. 2016 Jun 06;534(7608):494-9
27281198
Peptides. 2013 Jun;44:40-6
23523779
Trends Pharmacol Sci. 2010 Apr;31(4):175-82
20097434
Mol Pharmacol. 2010 Dec;78(6):1124-34
20855463
Nat Struct Mol Biol. 2014 Mar;21(3):244-52
24487958
Acta Naturae. 2014 Apr;6(2):84-94
25093115
Nature. 2003 May 1;423(6935):42-8
12721619
Annu Rev Entomol. 2013;58:475-96
23020618
Nature. 2008 Nov 13;456(7219):202-8
19005548
Nat Methods. 2007 Jun;4(6):467-8
17538627
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5463-70
25453087
J Mol Biol. 2015 Jan 16;427(1):158-75
25088688
J Biomol NMR. 2013 Jul;56(3):227-41
23728592
Nature. 2003 May 1;423(6935):33-41
12721618
Toxicon. 2010 Nov;56(6):849-54
20603141
J Am Chem Soc. 2003 Feb 19;125(7):1731-7
12580598