Molecular structures of the human Slo1 K+ channel in complex with β4

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Abstract

Slo1 is a Ca²⁺- and voltage-activated K⁺ channel that underlies skeletal and smooth muscle contraction, audition, hormone secretion and neurotransmitter release. In mammals, Slo1 is regulated by auxiliary proteins that confer tissue-specific gating and pharmacological properties. This study presents cryo-EM structures of Slo1 in complex with the auxiliary protein, β4. Four β4, each containing two transmembrane helices, encircle Slo1, contacting it through helical interactions inside the membrane. On the extracellular side, b4 forms a tetrameric crown over the pore. Structures with high and low Ca²⁺ concentrations show that identical gating conformations occur in the absence and presence of β4, implying that β4 serves to modulate the relative stabilities of 'pre-existing' conformations rather than creating new ones. The effects of β4 on scorpion toxin inhibition kinetics are explained by the crown, which constrains access but does not prevent binding.

Data availability

The B-factor sharpened 3D cryo-EM density maps and atomic coordinates of the Ca2+-bound (open) hsSlo1-beta4 complex (accession number EMD-21025 and 6V22), the Ca2+-free (closed) hsSlo1-beta4 complex (accession number EMD-21028 and 6V35), the Ca2+-bound (open) hsSlo1 (accession number EMD-21029 and 6V38), and the Ca2+-free (closed) hsSlo1 (accession number EMD-21036 and 6V3G) have been deposited in the Worldwide Protein Data Bank (wwPDB).

The following data sets were generated

1. Tao X
2. MacKinnon R
(2019) Single particle cryo-EM structure of Ca2+-bound (open) hsSlo1-beta4 complex
Protein Data Bank, EMD-21025 and PDB 6V22.

https://www.rcsb.org/structure/6V22
1. Tao X
2. MacKinnon R
(2019) Single particle cryo-EM structure of Ca2+-free (closed) hsSlo1-beta4 complex
Protein Data Bank, EMD-21028 and PDB 6V35.

https://www.rcsb.org/structure/6V35
1. Tao X
2. MacKinnon R
(2019) Single particle cryo-EM structure of Ca2+-bound (open) hsSlo1
Protein Data Bank, EMD-21029 and PDB 6V38.

https://www.rcsb.org/structure/6V38
1. Tao X
2. MacKinnon R
(2019) Single particle cryo-EM structure of Ca2+-free (closed) hsSlo1
Protein Data Bank, EMD-21036 and PDB 6V3G.

https://www.rcsb.org/structure/6V3G

Article and author information

Author details

Xiao Tao

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9381-7903
Roderick MacKinnon

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

For correspondence
mackinn@mail.rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7605-4679

Funding

National Institutes of Health (GM43949)

Roderick MacKinnon

Howard Hughes Medical Institute

Roderick MacKinnon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.