Mapping the receptor site for α-scorpion toxins on a Na + channel voltage sensor

Jinti Wang, Vladimir Yarov-Yarovoy, Roy Kahn, Dalia Gordon, Michael Gurevitz, Todd Scheuer, William A. Catterall

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

The α-scorpions toxins bind to the resting state of Na + channels and inhibit fast inactivation by interaction with a receptor site formed by domains I and IV. Mutants T1560A, F1610A, and E1613A in domain IV had lower affinities for Leiurus quinquestriatus hebraeus toxin II (LqhII), and mutant E1613R had ∼73-fold lower affinity. Toxin dissociation was accelerated by depolarization and increased by these mutations, whereas association rates at negative membrane potentials were not changed. These results indicate that Thr1560 in the S1-S2 loop, Phe1610 in the S3 segment, and Glu1613 in the S3-S4 loop in domain IV participate in toxin binding. T393A in the SS2-S6 loop in domain I also had lower affinity for LqhII, indicating that this extracellular loop may form a secondary component of the receptor site. Analysis with the Rosetta-Membrane algorithm resulted in a model of LqhII binding to the voltage sensor in a resting state, in which amino acid residues in an extracellular cleft formed by the S1-S2 and S3-S4 loops in domain IV interact with two faces of the wedge-shaped LqhII molecule. The conserved gating charges in the S4 segment are in an inward position and form ion pairs with negatively charged amino acid residues in the S2 and S3 segments of the voltage sensor. This model defines the structure of the resting state of a voltage sensor of Na + channels and reveals its mode of interaction with a gating modifier toxin.

Original languageEnglish (US)
Pages (from-to)15426-15431
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number37
DOIs
StatePublished - Sep 13 2011

Fingerprint

Charybdotoxin
Scorpions
S 6
Amino Acids
Membrane Potentials
Ions
Mutation
Membranes
scorpion toxin receptor

Keywords

  • Mutagenesis
  • Voltage-gated sodium channel

ASJC Scopus subject areas

  • General

Cite this

Mapping the receptor site for α-scorpion toxins on a Na + channel voltage sensor. / Wang, Jinti; Yarov-Yarovoy, Vladimir; Kahn, Roy; Gordon, Dalia; Gurevitz, Michael; Scheuer, Todd; Catterall, William A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 37, 13.09.2011, p. 15426-15431.

Research output: Contribution to journalArticle

Wang, Jinti ; Yarov-Yarovoy, Vladimir ; Kahn, Roy ; Gordon, Dalia ; Gurevitz, Michael ; Scheuer, Todd ; Catterall, William A. / Mapping the receptor site for α-scorpion toxins on a Na + channel voltage sensor. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 37. pp. 15426-15431.
@article{3e799cfd5af84f23820af043070117db,
title = "Mapping the receptor site for α-scorpion toxins on a Na + channel voltage sensor",
abstract = "The α-scorpions toxins bind to the resting state of Na + channels and inhibit fast inactivation by interaction with a receptor site formed by domains I and IV. Mutants T1560A, F1610A, and E1613A in domain IV had lower affinities for Leiurus quinquestriatus hebraeus toxin II (LqhII), and mutant E1613R had ∼73-fold lower affinity. Toxin dissociation was accelerated by depolarization and increased by these mutations, whereas association rates at negative membrane potentials were not changed. These results indicate that Thr1560 in the S1-S2 loop, Phe1610 in the S3 segment, and Glu1613 in the S3-S4 loop in domain IV participate in toxin binding. T393A in the SS2-S6 loop in domain I also had lower affinity for LqhII, indicating that this extracellular loop may form a secondary component of the receptor site. Analysis with the Rosetta-Membrane algorithm resulted in a model of LqhII binding to the voltage sensor in a resting state, in which amino acid residues in an extracellular cleft formed by the S1-S2 and S3-S4 loops in domain IV interact with two faces of the wedge-shaped LqhII molecule. The conserved gating charges in the S4 segment are in an inward position and form ion pairs with negatively charged amino acid residues in the S2 and S3 segments of the voltage sensor. This model defines the structure of the resting state of a voltage sensor of Na + channels and reveals its mode of interaction with a gating modifier toxin.",
keywords = "Mutagenesis, Voltage-gated sodium channel",
author = "Jinti Wang and Vladimir Yarov-Yarovoy and Roy Kahn and Dalia Gordon and Michael Gurevitz and Todd Scheuer and Catterall, {William A.}",
year = "2011",
month = "9",
day = "13",
doi = "10.1073/pnas.1112320108",
language = "English (US)",
volume = "108",
pages = "15426--15431",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "37",

}

TY - JOUR

T1 - Mapping the receptor site for α-scorpion toxins on a Na + channel voltage sensor

AU - Wang, Jinti

AU - Yarov-Yarovoy, Vladimir

AU - Kahn, Roy

AU - Gordon, Dalia

AU - Gurevitz, Michael

AU - Scheuer, Todd

AU - Catterall, William A.

PY - 2011/9/13

Y1 - 2011/9/13

N2 - The α-scorpions toxins bind to the resting state of Na + channels and inhibit fast inactivation by interaction with a receptor site formed by domains I and IV. Mutants T1560A, F1610A, and E1613A in domain IV had lower affinities for Leiurus quinquestriatus hebraeus toxin II (LqhII), and mutant E1613R had ∼73-fold lower affinity. Toxin dissociation was accelerated by depolarization and increased by these mutations, whereas association rates at negative membrane potentials were not changed. These results indicate that Thr1560 in the S1-S2 loop, Phe1610 in the S3 segment, and Glu1613 in the S3-S4 loop in domain IV participate in toxin binding. T393A in the SS2-S6 loop in domain I also had lower affinity for LqhII, indicating that this extracellular loop may form a secondary component of the receptor site. Analysis with the Rosetta-Membrane algorithm resulted in a model of LqhII binding to the voltage sensor in a resting state, in which amino acid residues in an extracellular cleft formed by the S1-S2 and S3-S4 loops in domain IV interact with two faces of the wedge-shaped LqhII molecule. The conserved gating charges in the S4 segment are in an inward position and form ion pairs with negatively charged amino acid residues in the S2 and S3 segments of the voltage sensor. This model defines the structure of the resting state of a voltage sensor of Na + channels and reveals its mode of interaction with a gating modifier toxin.

AB - The α-scorpions toxins bind to the resting state of Na + channels and inhibit fast inactivation by interaction with a receptor site formed by domains I and IV. Mutants T1560A, F1610A, and E1613A in domain IV had lower affinities for Leiurus quinquestriatus hebraeus toxin II (LqhII), and mutant E1613R had ∼73-fold lower affinity. Toxin dissociation was accelerated by depolarization and increased by these mutations, whereas association rates at negative membrane potentials were not changed. These results indicate that Thr1560 in the S1-S2 loop, Phe1610 in the S3 segment, and Glu1613 in the S3-S4 loop in domain IV participate in toxin binding. T393A in the SS2-S6 loop in domain I also had lower affinity for LqhII, indicating that this extracellular loop may form a secondary component of the receptor site. Analysis with the Rosetta-Membrane algorithm resulted in a model of LqhII binding to the voltage sensor in a resting state, in which amino acid residues in an extracellular cleft formed by the S1-S2 and S3-S4 loops in domain IV interact with two faces of the wedge-shaped LqhII molecule. The conserved gating charges in the S4 segment are in an inward position and form ion pairs with negatively charged amino acid residues in the S2 and S3 segments of the voltage sensor. This model defines the structure of the resting state of a voltage sensor of Na + channels and reveals its mode of interaction with a gating modifier toxin.

KW - Mutagenesis

KW - Voltage-gated sodium channel

UR - http://www.scopus.com/inward/record.url?scp=80053064950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053064950&partnerID=8YFLogxK

U2 - 10.1073/pnas.1112320108

DO - 10.1073/pnas.1112320108

M3 - Article

VL - 108

SP - 15426

EP - 15431

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 37

ER -