Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

Georg Kuenze; Carlos G. Vanoye; Reshma R. Desai; Sneha Adusumilli; Kathryn R. Brewer; Hope Woods; Eli F. McDonald; Charles R. Sanders; Alfred L. George; Jens Meiler

doi:10.7554/eLife.57680

Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

Georg Kuenze^*, Carlos G. Vanoye, Reshma R. Desai, Sneha Adusumilli, Kathryn R. Brewer, Hope Woods, Eli F. McDonald, Charles R. Sanders, Alfred L. George, Jens Meiler

^*Corresponding author for this work

Pharmacology

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

12 Scopus citations

Abstract

The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, I_Ks, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.

Original language	English (US)
Article number	e57680
Pages (from-to)	1-30
Number of pages	30
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.57680
State	Published - Oct 2020

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Neuroscience

Access to Document

10.7554/eLife.57680

Cite this

@article{757173ce355d469794fb89e28301d592,

title = "Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation",

abstract = "The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.",

author = "Georg Kuenze and Vanoye, {Carlos G.} and Desai, {Reshma R.} and Sneha Adusumilli and Brewer, {Kathryn R.} and Hope Woods and McDonald, {Eli F.} and Sanders, {Charles R.} and George, {Alfred L.} and Jens Meiler",

note = "Funding Information: This work was supported by NIH grants R01 HL122010 and R01 GM080403. GK was supported by fellowships from the German Research Foundation (KU 3510/1–1) and the American Heart Association (18POST34080422). EFM was supported by NIH training grant T32 GM065086. KRB was supported by NIH training grant T32 GM008320. This work was conducted using the resources of the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. JM further acknowledges the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through SFB1423, project number 421152132. Publisher Copyright: {\textcopyright} Kuenze et al.",

year = "2020",

month = oct,

doi = "10.7554/eLife.57680",

language = "English (US)",

volume = "9",

pages = "1--30",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

AU - Kuenze, Georg

AU - Vanoye, Carlos G.

AU - Desai, Reshma R.

AU - Adusumilli, Sneha

AU - Brewer, Kathryn R.

AU - Woods, Hope

AU - McDonald, Eli F.

AU - Sanders, Charles R.

AU - George, Alfred L.

AU - Meiler, Jens

N1 - Funding Information: This work was supported by NIH grants R01 HL122010 and R01 GM080403. GK was supported by fellowships from the German Research Foundation (KU 3510/1–1) and the American Heart Association (18POST34080422). EFM was supported by NIH training grant T32 GM065086. KRB was supported by NIH training grant T32 GM008320. This work was conducted using the resources of the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. JM further acknowledges the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through SFB1423, project number 421152132. Publisher Copyright: © Kuenze et al.

PY - 2020/10

Y1 - 2020/10

N2 - The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.

AB - The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.

UR - http://www.scopus.com/inward/record.url?scp=85094684453&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85094684453&partnerID=8YFLogxK

U2 - 10.7554/eLife.57680

DO - 10.7554/eLife.57680

M3 - Article

C2 - 33095155

AN - SCOPUS:85094684453

SN - 2050-084X

VL - 9

SP - 1

EP - 30

JO - eLife

JF - eLife

M1 - e57680

ER -

Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this