The Cm28 in the venom of Centruroides margaritatus is a short peptide consisting of 27 amino acid residues with a mol wt of 2,820 D. Cm28 has <40% similarity with other known α-KTx from scorpions and lacks the typical functional dyad (lysine–tyrosine) required to block KV channels. However, its unique sequence contains the three disulfide-bond traits of the α-KTx scorpion toxin family. We propose that Cm28 is the first example of a new subfamily of α-KTxs, registered with the systematic number α-KTx32.1. Cm28 inhibited voltage-gated K+ channels KV1.2 and KV1.3 with Kd values of 0.96 and 1.3 nM, respectively. There was no significant shift in the conductance–voltage (G-V) relationship for any of the channels in the presence of toxin. Toxin binding kinetics showed that the association and dissociation rates are consistent with a bimolecular interaction between the peptide and the channel. Based on these, we conclude that Cm28 is not a gating modifier but rather a pore blocker. In a selectivity assay, Cm28 at 150 nM concentration (>100× Kd value for KV1.3) did not inhibit KV1.5, KV11.1, KCa1.1, and KCa3.1 K+ channels; NaV1.5 and NaV1.4 Na+ channels; or the hHV1 H+ channel but blocked ∼27% of the KV1.1 current. In a biological functional assay, Cm28 strongly inhibited the expression of the activation markers interleukin-2 receptor and CD40 ligand in anti-CD3–activated human CD4+ effector memory T lymphocytes. Cm28, due to its unique structure, may serve as a template for the generation of novel peptides targeting KV1.3 in autoimmune diseases.
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June 14 2022
Cm28, a scorpion toxin having a unique primary structure, inhibits KV1.2 and KV1.3 with high affinity
Muhammad Umair Naseem,
Muhammad Umair Naseem
1
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
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Edson Carcamo-Noriega,
Edson Carcamo-Noriega
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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José Beltrán-Vidal
,
José Beltrán-Vidal
3
Grupo de Investigaciones Herpetológicas y Toxinológicas, Centro de Investigaciones Biomédicas, Departamento de Biología, Facultad de Ciencias Naturales, Exactas y de la Educación, Universidad del Cauca, Popayán, Colombia
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Jesus Borrego,
Jesus Borrego
1
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
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Tibor G. Szanto,
Tibor G. Szanto
1
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
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Fernando Z. Zamudio,
Fernando Z. Zamudio
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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Gustavo Delgado-Prudencio
,
Gustavo Delgado-Prudencio
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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Lourival D. Possani,
Lourival D. Possani
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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Gyorgy Panyi
1
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
Correspondence to Gyorgy Panyi: panyi@med.unideb.hu
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Muhammad Umair Naseem
1
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
Edson Carcamo-Noriega
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
José Beltrán-Vidal
3
Grupo de Investigaciones Herpetológicas y Toxinológicas, Centro de Investigaciones Biomédicas, Departamento de Biología, Facultad de Ciencias Naturales, Exactas y de la Educación, Universidad del Cauca, Popayán, Colombia
Jesus Borrego
1
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
Tibor G. Szanto
1
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
Fernando Z. Zamudio
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
Gustavo Delgado-Prudencio
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
Lourival D. Possani
2
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
Correspondence to Gyorgy Panyi: panyi@med.unideb.hu
This work is part of a special issue on Structure and Function of Ion Channels in Native Cells and Macromolecular Complexes.
Received:
March 09 2022
Accepted:
May 23 2022
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding
Funder(s):
Hungarian National Research, Development, and Innovation Office
- Award Id(s): K143071,K142612,K132906
Funder(s):
CONACYT National Council of Science and Technology of Mexico
- Award Id(s): 303045
Funder(s):
Stipendium Hungaricum Scholarship
Funder(s):
Tempus Public Foundation
© 2022 Naseem et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2022) 154 (8): e202213146.
Article history
Received:
March 09 2022
Accepted:
May 23 2022
Citation
Muhammad Umair Naseem, Edson Carcamo-Noriega, José Beltrán-Vidal, Jesus Borrego, Tibor G. Szanto, Fernando Z. Zamudio, Gustavo Delgado-Prudencio, Lourival D. Possani, Gyorgy Panyi; Cm28, a scorpion toxin having a unique primary structure, inhibits KV1.2 and KV1.3 with high affinity. J Gen Physiol 1 August 2022; 154 (8): e202213146. doi: https://doi.org/10.1085/jgp.202213146
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