KCNE1 Membrane Protein Introduction

Introduction of KCNE1

KCNE1, also known as potassium voltage-gated channel subfamily E regulatory subunit 1, potassium voltage-gated channel, Isk-related subfamily, member 1, cardiac delayed rectifier potassium channel protein, voltage-gated potassium channel accessory subunit, LQT2/5, JLNS2, JLNS, LQT5, MinK, and ISK, is an approximately 14.7 k Da transmembrane protein composed of 129 amino acids. In humans, it is encoded by the KCNE1 gene mapped to the chromosome 21q22.12. KCNE1 is detected to be expressed in human heart, also in kidneys and murine inner ears. Genomic sequence analysis determined this gene contains 3 exons and 2 introns. The first two exons encode 5-prime untranslated regions (UTR), while the third one contains the entire coding region and 3-prime UTR. And 2 introns reside in the 5-prime UTR. The KCNE1 coding region is relatively conserved: there is ~76% amino acid sequence identity between mouse and human.

Function of KCNE1 Membrane Protein

KCNE1 encodes a protein, which is known for modulating the cardiac and epithelial Kv channel α subunit, KCNQ1. KCNE1 and KCNQ1 can form a complex in human ventricular cardiomyocytes that generate the slowly activating K+ current, IKs. IKs plays a pivotal role in cardiac action potential repolarization, especially under repolarization stress. Mutations in the human KCNE1 gene would cause autosomal recessive Jervell, autosomal dominant Romano-Ward (RW), and Lange-Nielsen (JLN) forms of long QT syndromes. The KCNE1 protein can regulate the activity of potassium channels. The specific function of potassium channels is based on their protein components and location in the body. These channels, transporting positively charged potassium ions into and out of cells, play a central role in a cellular ability to generate and transmit electrical signals. Also, KCNE1 is reported to modulate two other KCNQ family α subunits, KCNQ4 and KCNQ5, by increasing both their peak currents in oocyte expressions and slowing the activation of the latter.

Fig.1 A cartoon of KCNE1, indicating the location of the LQT5 mutations and the deletions in the C-terminus. (Dvir, 2014)

Application of KCNE1 Membrane Protein in Literature

1. Yao H., et al. Mutation in KCNE1 associated to early repolarization syndrome by modulation of slowly activating delayed rectifier K⁺ current. Exp Cell Res. 2018, 363(2): 315-320. PubMed ID: 29395134
   
   

   The S38G mutation resulted in a loss-of-function of IKs because of decreased KCNE1 protein expression and defected in KCNE1 protein membrane trafficking. The findings of this study suggested that KCNE1 may be one of the possible modulatory genes related to early repolarization syndrome (ERS).

2. Wu M., et al. A novel role of the antitumor agent tricyclodecan-9-yl-xanthogenate as an open channel blocker of KCNQ1/KCNE1. Eur J Pharmacol. 2018, 824: 99-107. PubMed ID: 29438706
   
   

   This review identified tricyclodecan-9-yl-xanthogenate (D609) as a specific open channel blocker of KCNQ1/KCNE1. KCNQ1/KCNE1 was highly expressed in the pancreas, heart, and inner ear. D609 might affect the function of many organs in vivo even when used as an antitumor or antiviral drug at a low concentration.

3. Lane C.M., et al. Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant. Heart Rhythm. 2018, 15(8): 1223-1230. PubMed ID: 29625280
   
   

   The study provided further proof that relatively common variants in KCNE1 may lead to a mild QT phenotype named "LQT5-Lite" to distinguish such underlying proarrhythmic common variants from rare pathogenic variants that indeed conferred monogenic disease susceptibility, although with incomplete penetrance.

4. Villatoro-Gómez K., et al. Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline. Biochem Pharmacol. 2018, 152: 264-271. PubMed ID: 29621539
   
   

   The experimental results and modeling suggested that AMIT preferentially blocked the open state of Kv7.1/KCNE1 channels through interacting with specific residues that were formerly reported to be significant for binding of other compounds, for instance, chromanol 293B and benzodiazepine L7.

5. Zhang R., et al. Probing the interaction of the potassium channel modulating KCNE1 in lipid bilayers via solid-state NMR spectroscopy. Magn Reson Chem. 2017, 55(8): 754-758. PubMed ID: 28233402
   
   

   This paper investigated the dynamics of lipid bilayers upon incorporation of the membrane protein KCNE1 by using 31P solid-state nuclear magnetic resonance spectroscopy. Definitely, the protein/lipid interaction was studied at diverse molar ratios of protein to lipid content.

KCNE1 Preparation Options

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Reference

1. Dvir M, et al. (2014). Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIP2. J Cell Sci. 127(Pt 18): 3943-3955.

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