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.
Cm28, a scorpion toxin having a unique primary structure, inhibits KV1.2 and KV1.3 with high affinity
This work is part of a special issue on Structure and Function of Ion Channels in Native Cells and Macromolecular Complexes.
- Award Id(s): K143071,K142612,K132906
- Award Id(s): 303045
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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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