The S4 voltage sensor packs against the pore domain in the KAT1 voltage-gated potassium channel

Helen C. Lai; Michael Grabe; Nung Jan Yuh; Yeh Jan Lily

doi:10.1016/j.neuron.2005.06.019

The S4 voltage sensor packs against the pore domain in the KAT1 voltage-gated potassium channel

Helen C. Lai, Michael Grabe, Nung Jan Yuh, Yeh Jan Lily

Neuroscience

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

In voltage-gated ion channels, the S4 transmembrane segment responds to changes in membrane potential and controls channel opening. The local environment of S4 is still unknown, even regarding the basic question as to whether S4 is close to the pore domain. Relying on the ability of functional KAT1 channels to rescue potassium (K⁺) transport-deficient yeast, we have performed an unbiased mutagenesis screen aimed at determining whether S4 packs against S5 of the pore domain. Starting with semilethal mutations of surface-exposed S5 residues of the KAT1 pore domain, we have screened randomly mutagenized libraries of S4 or S1-S3 for second-site suppressors. Our study identifies two S4 residues that interact in a highly specific manner with two S5 residues in the middle of the membrane-spanning regions, supporting a model in which the S4 voltage sensor packs against the pore domain in the hyperpolarized, or "down," state of S4.

Original language	English (US)
Pages (from-to)	395-406
Number of pages	12
Journal	Neuron
Volume	47
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2005.06.019
State	Published - Aug 4 2005

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2005.06.019

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title = "The S4 voltage sensor packs against the pore domain in the KAT1 voltage-gated potassium channel",

abstract = "In voltage-gated ion channels, the S4 transmembrane segment responds to changes in membrane potential and controls channel opening. The local environment of S4 is still unknown, even regarding the basic question as to whether S4 is close to the pore domain. Relying on the ability of functional KAT1 channels to rescue potassium (K+) transport-deficient yeast, we have performed an unbiased mutagenesis screen aimed at determining whether S4 packs against S5 of the pore domain. Starting with semilethal mutations of surface-exposed S5 residues of the KAT1 pore domain, we have screened randomly mutagenized libraries of S4 or S1-S3 for second-site suppressors. Our study identifies two S4 residues that interact in a highly specific manner with two S5 residues in the middle of the membrane-spanning regions, supporting a model in which the S4 voltage sensor packs against the pore domain in the hyperpolarized, or {"}down,{"} state of S4.",

author = "Lai, {Helen C.} and Michael Grabe and Yuh, {Nung Jan} and Lily, {Yeh Jan}",

note = "Funding Information: We would like to thank Dr. J.I. Schroeder for the KAT1 construct; Dr. S. Kurtz for providing the yeast strain; Dr. D. Minor for valuable experimental guidance; Dr. D. Bichet, Dr. B. Cohen, A. Fay, Dr. C. Gu, F. Haass, P. Haddick, Dr. B. Schroeder, T. Surti, Dr. B. Tu, and members of the Jan Lab for their support, helpful advice, and input at all stages of this project. H.C.L. is supported by an American Heart Association Pre-doctoral Fellowship, Western States Affiliate and was supported by an NIH Structural Biology Training Grant GM08284. M.G. is supported by a National Science Foundation Interdisciplinary Informatics Fellowship. Y.N.J. and L.Y.J. are HHMI investigators. This study is supported by an R01 grant from the NIMH. The authors declare no competing interests. ",

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AU - Lai, Helen C.

AU - Grabe, Michael

AU - Yuh, Nung Jan

AU - Lily, Yeh Jan

N1 - Funding Information: We would like to thank Dr. J.I. Schroeder for the KAT1 construct; Dr. S. Kurtz for providing the yeast strain; Dr. D. Minor for valuable experimental guidance; Dr. D. Bichet, Dr. B. Cohen, A. Fay, Dr. C. Gu, F. Haass, P. Haddick, Dr. B. Schroeder, T. Surti, Dr. B. Tu, and members of the Jan Lab for their support, helpful advice, and input at all stages of this project. H.C.L. is supported by an American Heart Association Pre-doctoral Fellowship, Western States Affiliate and was supported by an NIH Structural Biology Training Grant GM08284. M.G. is supported by a National Science Foundation Interdisciplinary Informatics Fellowship. Y.N.J. and L.Y.J. are HHMI investigators. This study is supported by an R01 grant from the NIMH. The authors declare no competing interests.

PY - 2005/8/4

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N2 - In voltage-gated ion channels, the S4 transmembrane segment responds to changes in membrane potential and controls channel opening. The local environment of S4 is still unknown, even regarding the basic question as to whether S4 is close to the pore domain. Relying on the ability of functional KAT1 channels to rescue potassium (K+) transport-deficient yeast, we have performed an unbiased mutagenesis screen aimed at determining whether S4 packs against S5 of the pore domain. Starting with semilethal mutations of surface-exposed S5 residues of the KAT1 pore domain, we have screened randomly mutagenized libraries of S4 or S1-S3 for second-site suppressors. Our study identifies two S4 residues that interact in a highly specific manner with two S5 residues in the middle of the membrane-spanning regions, supporting a model in which the S4 voltage sensor packs against the pore domain in the hyperpolarized, or "down," state of S4.

AB - In voltage-gated ion channels, the S4 transmembrane segment responds to changes in membrane potential and controls channel opening. The local environment of S4 is still unknown, even regarding the basic question as to whether S4 is close to the pore domain. Relying on the ability of functional KAT1 channels to rescue potassium (K+) transport-deficient yeast, we have performed an unbiased mutagenesis screen aimed at determining whether S4 packs against S5 of the pore domain. Starting with semilethal mutations of surface-exposed S5 residues of the KAT1 pore domain, we have screened randomly mutagenized libraries of S4 or S1-S3 for second-site suppressors. Our study identifies two S4 residues that interact in a highly specific manner with two S5 residues in the middle of the membrane-spanning regions, supporting a model in which the S4 voltage sensor packs against the pore domain in the hyperpolarized, or "down," state of S4.

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The S4 voltage sensor packs against the pore domain in the KAT1 voltage-gated potassium channel

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