Tethered peptide neurotoxins display two blocking mechanisms in the K+ channel pore as do their untethered analogs

Ruiming Zhao, Hui Dai, Netanel Mendelman, Jordan H. Chill, Steve A.N. Goldstein

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

We show here that membrane-tethered toxins facilitate the biophysical study of the roles of toxin residues in K+ channel blockade to reveal two blocking mechanisms in the K+ channel pore. The structure of the sea anemone type I (SAK1) toxin HmK is determined by NMR. T-HmK residues are scanned by point mutation to map the toxin surface, and seven residues are identified to be critical to occlusion of the KcsA channel pore. T-HmK-Lys22 is shown to interact with K+ ions traversing the KcsA pore from the cytoplasm conferring voltage dependence on the toxin off rate, a classic mechanism that we observe as well with HmK in solution and for Kv1.3 channels. In contrast, two related SAK1 toxins, Hui1 and ShK, block KcsA and Kv1.3, respectively, via an arginine rather than the canonical lysine, when tethered and as free peptides.

Original languageEnglish
Article numbereaaz3439
JournalScience advances
Volume6
Issue number10
DOIs
StatePublished - Mar 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Funding

Funding: We are grateful for grant support from the NIH (GM111716 to S.A.N.G.) and the United States-Israel Binational Science Foundation (BSF 2013185 and 2017243) to S.A.N.G. and J.H.C.

FundersFunder number
National Institutes of Health
National Institute of General Medical SciencesR01GM111716
United States-Israel Binational Science Foundation2017243, BSF 2013185

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