# KCNE1

## Overview
The KCNE1 gene encodes the potassium voltage-gated channel subfamily E regulatory subunit 1, a critical component in the modulation of cardiac and auditory potassium channels. This gene is primarily known for its role in forming the slow delayed rectifier potassium current (I_Ks) by interacting with the KCNQ1 channel, which is essential for cardiac repolarization and electrical stability (Jiang2009Dynamic; Abbott2016KCNE1). The KCNE1 protein is a single-span transmembrane protein that influences the gating kinetics of the KCNQ1 channel, thereby affecting cardiac action potentials and reducing the risk of arrhythmias (Abbott2016KCNE1). Beyond its cardiac functions, KCNE1 is also expressed in the inner ear, where it plays a vital role in potassium ion transport, crucial for normal hearing (Abbott2016KCNE1). Mutations in KCNE1 are linked to various clinical conditions, including Long QT Syndrome and Jervell and Lange-Nielsen syndrome, highlighting its significance in both cardiac and auditory physiology (Nof2011LQT5; Faridi2018Mutational).

## Structure
The KCNE1 protein is a single-span membrane protein that modulates the KCNQ1 potassium channel. It consists of a transmembrane domain (TMD) that is helical and slightly curved, with the curvature being an intrinsic property observed in various environments such as micelles and lipid bilayers (Kang2008Structure; Sahu2014Structural). The TMD is flanked by flexible intra- and extracellular domains, allowing structural adaptation to its environment (Kang2008Structure). The extracellular end of the TMD forms an interface with the KCNQ1 channel, which is crucial for its modulatory function (Kang2008Structure).

The KCNE1 protein also features a three amino acid motif (F57-T58-L59) within its TMD, which is essential for the slow activation of the KCNQ1-KCNE1 channels. This motif interacts with specific sites in the KCNQ1 channel, affecting its gating properties through an allosteric mechanism (Kuenze2020Allosteric). The protein's structure is further characterized by flexibly linked alpha helices in the extramembrane N-terminal and C-terminal domains, which may undergo structural rearrangements upon binding to the KCNQ1 channel (Van2011Working). The KCNE1 protein is subject to post-translational modifications such as phosphorylation, which can influence its function.

## Function
The KCNE1 gene encodes a regulatory subunit that plays a crucial role in modulating voltage-gated potassium channels, particularly in association with the KCNQ1 channel. This interaction forms the slow delayed rectifier potassium current (I_Ks), which is essential for cardiac repolarization and maintaining the heart's electrical stability (Jiang2009Dynamic; Abbott2016KCNE1). KCNE1 influences the gating kinetics of the KCNQ1 channel by slowing its activation and deactivation, increasing conductance, and eliminating inactivation, which results in increased peak currents at positive voltages (Abbott2016KCNE1).

In cardiac cells, the KCNE1-KCNQ1 complex is vital for the repolarization of ventricular myocytes, particularly during physical exertion when β-adrenergic stimulation increases I_Ks density (Abbott2016KCNE1). This function is critical for preventing excessive prolongation of the cardiac action potential, thereby reducing the risk of arrhythmias (Jiang2009Dynamic).

KCNE1 is also expressed in the inner ear, where it contributes to potassium ion transport and recycling in the endolymph, a process crucial for normal hearing. Disruption of this function can lead to sensorineural deafness (Abbott2016KCNE1). The protein is active in cell membranes, influencing ion flow and electrical signaling in both cardiac and auditory cells (Lundquist2006Expression).

## Clinical Significance
Mutations in the KCNE1 gene are associated with several cardiac and auditory conditions. Jervell and Lange-Nielsen syndrome (JLNS) is a cardio-auditory disorder caused by biallelic pathogenic variants of KCNE1. It is characterized by congenital profound sensorineural deafness and a prolonged QT interval, which can lead to ventricular arrhythmias and sudden cardiac death (Faridi2018Mutational). Romano-Ward syndrome (RWS) is another condition linked to KCNE1 mutations, where heterozygous missense variants result in prolonged QT intervals and an increased risk of arrhythmias and sudden death through a dominant negative mechanism (Faridi2018Mutational).

The D85N polymorphism in KCNE1 is identified as a disease-causing variant in Long QT Syndrome (LQTS), significantly affecting cardiac repolarization by causing a loss-of-function effect on potassium channel currents (Nof2011LQT5; Nishio2009D85N). This polymorphism can also lead to LQT2 by interacting with KCNH2, reducing IKr current (Nof2011LQT5).

Mutations in KCNE1, such as G25V and G60D, have been linked to early-onset familial atrial fibrillation (AF), with these mutations causing a gain-of-function in potassium currents, potentially increasing susceptibility to AF (Olesen2012Mutations).

## Interactions
KCNE1, a regulatory subunit, interacts with the KCNQ1 potassium channel to form the I_Ks channel complex, which is crucial for cardiac repolarization. The interaction between KCNE1 and KCNQ1 involves multiple contact points, including the transmembrane domains and C-terminal cytoplasmic regions. These interactions modulate the channel's activation and deactivation kinetics, affecting the slowly activating K+ current (I_Ks) (Melman2004KCNE1; Zheng2010Analysis).

Surface plasmon resonance (SPR) and co-immunoprecipitation experiments have confirmed the physical interaction between the C-terminal domains of KCNE1 and KCNQ1, with specific regions of KCNQ1 (amino acids 349-438) being critical for binding (Zheng2010Analysis). The KCNE1 C-terminus can alter the voltage-dependent deactivation and inactivation of KCNQ1 channels, as demonstrated by voltage clamp analysis (Zheng2010Analysis).

Molecular dynamics simulations have shown that KCNE1 stabilizes the KCNQ1 channel by reducing its backbone flexibility, particularly in the S5-P linker region, through allosteric mechanisms (Xu2013Building). These interactions are essential for the proper regulation of the channel's function and are implicated in conditions such as Long QT Syndrome (LQTS) (Chen2020Physical).


## References


[1. (Faridi2018Mutational) Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, December 2018. URL: http://dx.doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 11 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.23689)

[2. (Jiang2009Dynamic) Min Jiang, Xulin Xu, Yuhong Wang, Futoshi Toyoda, Xian-Sheng Liu, Mei Zhang, Richard B. Robinson, and Gea-Ny Tseng. Dynamic partnership between kcnq1 and kcne1 and influence on cardiac iks current amplitude by kcne2. Journal of Biological Chemistry, 284(24):16452–16462, June 2009. URL: http://dx.doi.org/10.1074/jbc.m808262200, doi:10.1074/jbc.m808262200. This article has 53 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m808262200)

[3. (Chen2020Physical) Jerri Chen, Zhenning Liu, John Creagh, Renjian Zheng, and Thomas V. McDonald. Physical and functional interaction sites in cytoplasmic domains of kcnq1 and kcne1 channel subunits. American Journal of Physiology-Heart and Circulatory Physiology, 318(2):H212–H222, February 2020. URL: http://dx.doi.org/10.1152/ajpheart.00459.2019, doi:10.1152/ajpheart.00459.2019. This article has 7 citations.](https://doi.org/10.1152/ajpheart.00459.2019)

[4. (Olesen2012Mutations) Morten S Olesen, Bo H Bentzen, Jonas B Nielsen, Annette B Steffensen, Jens-Peter David, Javad Jabbari, Henrik K Jensen, Stig Haunsø, Jesper H Svendsen, and Nicole Schmitt. Mutations in the potassium channel subunit kcne1 are associated with early-onset familial atrial fibrillation. BMC Medical Genetics, April 2012. URL: http://dx.doi.org/10.1186/1471-2350-13-24, doi:10.1186/1471-2350-13-24. This article has 74 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/1471-2350-13-24)

[5. (Abbott2016KCNE1) Geoffrey W. Abbott. Kcne1 and kcne3: the yin and yang of voltage-gated k+ channel regulation. Gene, 576(1):1–13, January 2016. URL: http://dx.doi.org/10.1016/j.gene.2015.09.059, doi:10.1016/j.gene.2015.09.059. This article has 62 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.gene.2015.09.059)

[6. (Nishio2009D85N) Yukiko Nishio, Takeru Makiyama, Hideki Itoh, Tomoko Sakaguchi, Seiko Ohno, Yin-Zhi Gong, Satoshi Yamamoto, Tomoya Ozawa, Wei-Guang Ding, Futoshi Toyoda, Mihoko Kawamura, Masaharu Akao, Hiroshi Matsuura, Takeshi Kimura, Toru Kita, and Minoru Horie. D85n, a kcne1 polymorphism, is a disease-causing gene variant in long qt syndrome. Journal of the American College of Cardiology, 54(9):812–819, August 2009. URL: http://dx.doi.org/10.1016/j.jacc.2009.06.005, doi:10.1016/j.jacc.2009.06.005. This article has 137 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.jacc.2009.06.005)

[7. (Lundquist2006Expression) Andrew L. Lundquist, Candice L. Turner, Leomar Y. Ballester, and Alfred L. George. Expression and transcriptional control of human kcne genes. Genomics, 87(1):119–128, January 2006. URL: http://dx.doi.org/10.1016/j.ygeno.2005.09.004, doi:10.1016/j.ygeno.2005.09.004. This article has 36 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ygeno.2005.09.004)

[8. (Nof2011LQT5) E. Nof, H. Barajas-Martinez, M. Eldar, J. Urrutia, G. Caceres, G. Rosenfeld, D. Bar-Lev, M. Feinberg, E. Burashnikov, O. Casis, D. Hu, M. Glikson, and C. Antzelevitch. Lqt5 masquerading as lqt2: a dominant negative effect of kcne1-d85n rare polymorphism on kcnh2 current. Europace, 13(10):1478–1483, June 2011. URL: http://dx.doi.org/10.1093/europace/eur184, doi:10.1093/europace/eur184. This article has 20 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/europace/eur184)

[9. (Kang2008Structure) Congbao Kang, Changlin Tian, Frank D. Sönnichsen, Jarrod A. Smith, Jens Meiler, Alfred L. George, Carlos G. Vanoye, Hak Jun Kim, and Charles R. Sanders. Structure of kcne1 and implications for how it modulates the kcnq1 potassium channel. Biochemistry, 47(31):7999–8006, July 2008. URL: http://dx.doi.org/10.1021/bi800875q, doi:10.1021/bi800875q. This article has 164 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi800875q)

[10. (Melman2004KCNE1) Yonathan F. Melman, Sung Yon Um, Andrew Krumerman, Anna Kagan, and Thomas V. McDonald. Kcne1 binds to the kcnq1 pore to regulate potassium channel activity. Neuron, 42(6):927–937, June 2004. URL: http://dx.doi.org/10.1016/j.neuron.2004.06.001, doi:10.1016/j.neuron.2004.06.001. This article has 112 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.neuron.2004.06.001)

[11. (Xu2013Building) Yu Xu, Yuhong Wang, Xuan-Yu Meng, Mei Zhang, Min Jiang, Meng Cui, and Gea-Ny Tseng. Building kcnq1/kcne1 channel models and probing their interactions by molecular-dynamics simulations. Biophysical Journal, 105(11):2461–2473, December 2013. URL: http://dx.doi.org/10.1016/j.bpj.2013.09.058, doi:10.1016/j.bpj.2013.09.058. This article has 46 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.bpj.2013.09.058)

[12. (Zheng2010Analysis) Renjian Zheng, Keith Thompson, Edmond Obeng-Gyimah, Dana Alessi, Jerri Chen, Huiyong Cheng, and Thomas V. McDonald. Analysis of the interactions between the c-terminal cytoplasmic domains of kcnq1 and kcne1 channel subunits. Biochemical Journal, 428(1):75–84, April 2010. URL: http://dx.doi.org/10.1042/BJ20090977, doi:10.1042/bj20090977. This article has 44 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/BJ20090977)

[13. (Kuenze2020Allosteric) Georg Kuenze, Carlos G Vanoye, Reshma R Desai, Sneha Adusumilli, Kathryn R Brewer, Hope Woods, Eli F McDonald, Charles R Sanders, Alfred L George, and Jens Meiler. Allosteric mechanism for kcne1 modulation of kcnq1 potassium channel activation. eLife, October 2020. URL: http://dx.doi.org/10.7554/elife.57680, doi:10.7554/elife.57680. This article has 19 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.7554/elife.57680)

[14. (Sahu2014Structural) Indra D. Sahu, Brett M. Kroncke, Rongfu Zhang, Megan M. Dunagan, Hubbell J. Smith, Andrew Craig, Robert M. McCarrick, Charles R. Sanders, and Gary A. Lorigan. Structural investigation of the transmembrane domain of kcne1 in proteoliposomes. Biochemistry, 53(40):6392–6401, October 2014. URL: http://dx.doi.org/10.1021/bi500943p, doi:10.1021/bi500943p. This article has 39 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi500943p)

[15. (Van2011Working) Wade D Van Horn, Carlos G Vanoye, and Charles R Sanders. Working model for the structural basis for kcne1 modulation of the kcnq1 potassium channel. Current Opinion in Structural Biology, 21(2):283–291, April 2011. URL: http://dx.doi.org/10.1016/j.sbi.2011.01.001, doi:10.1016/j.sbi.2011.01.001. This article has 25 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.sbi.2011.01.001)