A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel

Cheng Tang, Xi Zhou, Phuong Tran Nguyen, Yunxiao Zhang, Zhaotun Hu, Changxin Zhang, Vladimir Yarov-Yarovoy, Paul G. DeCaen, Songping Liang, Zhonghua Liu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Voltage-gated sodiumchannels (NaVs) are activated by transiting the voltage sensor from thedeactivated to the activated state. The crystal structures of several bacterial NaVs have captured the voltage sensor module (VSM) in an activated state, but structure of the deactivated voltage sensor remains elusive. In this study,we sought to identify peptide toxins stabilizing the deactivated VSM of bacterial NaVs. We screened fractions from several venoms and characterized a cystine knot toxin called JZTx-27 from the venom of tarantula Chilobrachys jingzhao as a high-affinity antagonist of the prokaryotic NaVs NsVBa (nonselective voltage-gated Bacillus alcalophilus) and NaChBac (bacterial sodium channel from Bacillus halodurans) (IC50 = 112 nM and 30 nM, respectively). JZTx-27 was more efficacious at weaker depolarizing voltages and significantly slowed the activation but accelerated the deactivation of NsVBa, whereas the local anesthetic drug lidocaine was shown to antagonize NsVBa without affecting channel gating. Mutation analysis confirmed that JZTx-27 bound to S3-4 linker of NsVBa, with F98 being the critical residue in determining toxin affinity. All electrophysiological data and in silico analysis suggested that JZTx-27 trapped VSM of NsVBain one of the deactivatedstates. InmammalianNaVs, JZTx-27preferably inhibitedthe inactivation of NaV1.5 by targeting the fourth transmembrane domain. To our knowledge, this is the first report of peptide antagonist for prokaryotic NaVs. More important, we proposed that JZTx-27 stabilized the NsVBa VSM in the deactivated state and may be used as a probe to determine the structure of the deactivated VSM of NaVs.

Original languageEnglish (US)
Pages (from-to)3167-3178
Number of pages12
JournalFASEB Journal
Volume31
Issue number7
DOIs
StatePublished - Jul 1 2017

Keywords

  • Deactivated state
  • NsVBa
  • Peptide toxin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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