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A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel.
FASEB J. 2017 07; 31(7):3167-3178.FJ

Abstract

Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated 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 NsVBa in one of the deactivated states. In mammalian NaVs, JZTx-27 preferably inhibited the 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.-Tang, C., Zhou, X., Nguyen, P. T., Zhang, Y., Hu, Z., Zhang, C., Yarov-Yarovoy, V., DeCaen, P. G., Liang, S., Liu, Z. A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel.

Authors+Show Affiliations

The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.Department of Physiology and Membrane Biology, University of California Davis, Davis, California, USA.The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.Department of Physiology and Membrane Biology, University of California Davis, Davis, California, USA.Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA liangsp@hunnu.edu.cn liuzh@hunnu.edu.cn.The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China; liangsp@hunnu.edu.cn.The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China; liuzh@hunnu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28400471

Citation

Tang, Cheng, et al. "A Novel Tarantula Toxin Stabilizes the Deactivated Voltage Sensor of Bacterial Sodium Channel." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 31, no. 7, 2017, pp. 3167-3178.
Tang C, Zhou X, Nguyen PT, et al. A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel. FASEB J. 2017;31(7):3167-3178.
Tang, C., Zhou, X., Nguyen, P. T., Zhang, Y., Hu, Z., Zhang, C., Yarov-Yarovoy, V., DeCaen, P. G., Liang, S., & Liu, Z. (2017). A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 31(7), 3167-3178. https://doi.org/10.1096/fj.201600882R
Tang C, et al. A Novel Tarantula Toxin Stabilizes the Deactivated Voltage Sensor of Bacterial Sodium Channel. FASEB J. 2017;31(7):3167-3178. PubMed PMID: 28400471.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel. AU - Tang,Cheng, AU - Zhou,Xi, AU - Nguyen,Phuong Tran, AU - Zhang,Yunxiao, AU - Hu,Zhaotun, AU - Zhang,Changxin, AU - Yarov-Yarovoy,Vladimir, AU - DeCaen,Paul G, AU - Liang,Songping, AU - Liu,Zhonghua, Y1 - 2017/04/11/ PY - 2016/09/01/received PY - 2017/03/27/accepted PY - 2017/4/13/pubmed PY - 2017/9/19/medline PY - 2017/4/13/entrez KW - NsVBa KW - deactivated state KW - peptide toxin SP - 3167 EP - 3178 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 31 IS - 7 N2 - Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated 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 NsVBa in one of the deactivated states. In mammalian NaVs, JZTx-27 preferably inhibited the 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.-Tang, C., Zhou, X., Nguyen, P. T., Zhang, Y., Hu, Z., Zhang, C., Yarov-Yarovoy, V., DeCaen, P. G., Liang, S., Liu, Z. A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/28400471/A_novel_tarantula_toxin_stabilizes_the_deactivated_voltage_sensor_of_bacterial_sodium_channel_ L2 - https://doi.org/10.1096/fj.201600882R DB - PRIME DP - Unbound Medicine ER -