TCDB is operated by the Saier Lab Bioinformatics Group

8.A.10 The Slow Voltage-gated K+ Channel Accessory Protein (MinK or KCNE) Family

The MinK family, also called the KCNE family, is a small family of K+-selective channel accessory proteins found only in animals. MinK proteins are associated with and essential for the activities of K+ channel proteins such as the KvLQT1 protein (TC #1.A.1.15.1; VIC superfamily) encoded by the human LQT1 gene. A VIC superfamily (TC #1.A.1) member and the KvLQT1/MinK assembly generate the slowly activating K+ channel IKs. Some of these channels respond to a change in voltage very slowly; the current may reach its steady state only after 50 seconds.  The KCNQ1 channel is differentially regulated by KCNE1 and KCNE2 (Li et al. 2014).  KCNE2 exhibits an array of functions in the heart, stomach, thyroid and choroid plexus. A variety of interconnected disease manifestations caused by KCNE2 disruption involve both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia (Abbott 2015).

All sequenced MinK members are from mammals and are very similar. There are at least two isoforms, one found in intestinal or kidney epithelia, the other in cardiac tissue. MinK proteins are small (about 130 amino acids) with a single N-terminal transmembrane α-helical spanner, approximately at residues 45-65. The N-termini are extracellular while the large C-terminal tails are in the cytoplasm. The extracellular domains are glycosylated, and the activities of the proteins are regulated by phosphorylation of the cytoplasmic domains. They probably form heterooligomeric complexes and thereby modulate channel activity. There is evidence that residues in the MinK polypeptide chain are in close proximity to TMS6 in the channel complex, but are outside of the permeation pathway (Tapper and George, 2001). They not only affect channel gating and ion conduction, they also are required for efficient trafficking and cell surface expression (Chandrasekhar et al., 2006).  There are two MinK subunits (a dimer of β) per tetrameric channel complex (Morin and Kobertz, 2008).

KCNE genes (KCNE1-5) encode a family of subunits affecting channel activity.  Lundquist et al. 2006 mapped transcription start sites, delineated 5' genomic structure, and characterized functional promoter elements for each gene. They also identified alternatively spliced transcripts for both KCNE1 and KCNE3, including a cardiac-specific KCNE1 transcript. Analysis of relative expression levels of KCNE1-5 in a panel of human tissues revealed distinct, but overlapping, expression patterns. The coexpression of multiple functionally distinct KCNE genes in some tissues inferred complex accessory subunit modification of potassium channels (Lundquist et al. 2006).  The involvement of channel auxiliary subunits in channel regulation and cancer has been reviewed (Haworth and Brackenbury 2019).

KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv α subunits, hERG and KCNQ1, in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to the speculation that they form a native channel complex there. The murine kcne2 gene has been disrupted (Roepke et al., 2006). kcne2 (-/-) mice have a severe gastric phenotype with reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. Thus, KCNE2 is essential for gastric acid secretion (Roepke et al., 2006). KCNE genes are expressed in the human heart with a relative abundance ranking of KCNE1 > KCNE4 > KCNE5 ~= KCNE3 >> KCNE2 (Lundquist et al. 2005). In situ hybridization revealed prominent expression of KCNE1 and KCNE3-5 in human atrial myocytes. In cardiomyopathic hearts, expression of KCNE1, KCNE3, KCNE4, and KCNQ1 was increased, while KCNE2 and KCNE5 exhibited reduced expression. In a cell line stably expressing KCNQ1 and KCNE1, transient expression of KCNE3, KCNE4, or KCNE5 altered I(Ks) current profiles. Even in the presence of additional KCNE1, KCNE4 and KCNE5 exert dominant effects on I(Ks). Although KCNE1 is the predominant KCNE family member expressed in the human heart, the abundance of other KCNE transcripts including potential KCNQ1 suppressors (KCNE4 and KCNE5) and their altered expression patterns in disease suggest that a balance of KCNE accessory subunits may be important for cardiac K(V) channel function (Lundquist et al. 2005).

N-Glycosylation of membrane proteins is critical for their proper folding, co-assembly and subsequent matriculation through the secretory pathway. Bas et al. (2011) examined the kinetics of N-glycan addition to type I transmembrane KCNE1 K+ channel β-subunits, where point mutations that prevent N-glycosylation at one consensus site give rise to disorders of the cardiac rhythm and congenital deafness. KCNE1 has two distinct N-glycosylation sites: a typical co-translational site and a consensus site ∼20 residues away that unexpectedly acquires N-glycans after protein synthesis (post-translational). Mutations that ablate the co-translational site concomitantly reduce glycosylation at the post-translational site, resulting in unglycosylated KCNE1 subunits that cannot reach the cell surface with their cognate K+ channel. This long range inhibition is highly specific for post-translational N-glycosylation because mutagenic conversion of the KCNE1 post-translational site into a co-translational site restores both monoglycosylation and anterograde trafficking (Bas et al., 2011).

Accessory β-subunits of the KCNE gene family modulate the function of various cation channel α-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs (TC# 8.A.10.1.1) are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 form native I(Ks) channels. Strutz-Seebohm et al. (2011) characterized molecular determinants of the KCNE1 interaction with KCNQ1 channels. KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane α-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac I(Ks) channels.

Voltage-gated potassium (Kv) channels comprise pore-forming α-subunits and a multiplicity of regulatory proteins, including the cardiac-expressed and cardiac arrhythmia-linked transmembrane KCNE subunits. N-terminally extended (L) KCNE3 and KCNE4 isoforms regulate human cardiac Kv channel α-subunits (Abbott 2016). As for short isoforms, KCNE3S and KCNE4S, KCNE3L inhibits hERG; KCNE4L inhibits Kv1.1; neither form regulats the HCN1 pacemaker channel. Unlike KCNE4S, KCNE4L is a potent inhibitor of Kv4.2 and Kv4.3. Co-expression of cytosolic β-subunit KChIP2, which regulates Kv4 channels in cardiac myocytes, partially relieves Kv4.3 but not Kv4.2 inhibition. Inhibition of Kv4.2 and Kv4.3 by KCNE3L was weaker, and its inhibition of Kv4.2 was abolished by KChIP2. KCNE3L and KCNE4L also exhibited subunit-specific effects on Kv4 channel complex inactivation kinetics, voltage dependence and recovery. KCNE4L co- localized with Kv4.3 in human atrium (Abbott 2016).

In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) that controls the repolarization phase of cardiacaction potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range. They are important for controlling water and salt secretion and absorption (Barro-Soria et al. 2017). This difference between these two KCNE subunits is due to the fact that they affect different gating transitions (Barro-Soria et al. 2017).

KCNQ1 (Q1) is a voltage-gated potassium channel that is modulated by members of the KCNE family, the best-characterized being KCNE1 (E1) and KCNE3 (E3). The Q1/E1 complex generates a channel with delayed activation and increased conductance. This complex is expressed in cardiomyocytes where it provides the IKs current that is critical for the repolarization phase of the cardiac action potential. The Q1/E3 complex, on the other hand, is expressed in epithelial cells of the colon and stomach, where it serves as a constitutively active leak channel to help maintain water and ion homeostasis. Studies show the single transmembrane segments (TMS) present in both E1 and E3 are essential to their distinct functions. More specifically, residues FTL located near the middle of the E1 TMS are essential for the delayed activation of Q1, while the corresponding TVG sites in E3 are critical for constitutive activation of the channe (Law and Sanders 2019).

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 the slow activation. Kuenze et al. 2020 developed structural models of the complex that suggested 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 via an allosteric mechanism. A common transmembrane-binding mode for different KCNEs was suggested, which illuminates how specific differences in the interaction of their triplet motifs may determine the differences in KCNQ1 functional modulation by KCNE1 versus KCNE3 (Kuenze et al. 2020).

The generalized transport reaction catalyzed by MinK in complexation with other channel proteins is:

K+ (in)  → K+ (out)

References associated with 8.A.10 family:

and Abbott GW. (2015). The KCNE2 K(+) channel regulatory subunit: Ubiquitous influence, complex pathobiology. Gene. 569(2):162-72. 26123744
and Abbott GW. (2016). KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation. Gene. 576(1 Pt 1):1-13. 26410412
Abbott, G.W. (2016). Regulation of human cardiac potassium channels by full-length KCNE3 and KCNE4. Sci Rep 6: 38412. 27922120
Abbott, G.W., B. Ramesh, and S.K. Srai. (2008). Secondary structure of the MiRP1 (KCNE2) potassium channel ancillary subunit. Protein Pept Lett 15: 63-75. 18221016
Angelo, K., T. Jespersen, M. Grunnet, M.S. Nielsen, D.A. Klaerke, and S.P. Olesen. (2002). KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current. Biophys. J. 83: 1997-2006. 12324418
Asare, I.K., A.P. Galende, A.B. Garcia, M.F. Cruz, A.C.M. Moura, C.C. Campbell, M. Scheyer, J.P. Alao, S. Alston, A.N. Kravats, C.R. Sanders, G.A. Lorigan, and I.D. Sahu. (2022). Investigating Structural Dynamics of KCNE3 in Different Membrane Environments Using Molecular Dynamics Simulations. Membranes (Basel) 12:. 35629795
Barro-Soria, R., R. Ramentol, S.I. Liin, M.E. Perez, R.S. Kass, and H.P. Larsson. (2017). KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions. Proc. Natl. Acad. Sci. USA 114: E7367-E7376. 28808020
Bas, T., G.Y. Gao, A. Lvov, K.D. Chandrasekhar, R. Gilmore, and W.R. Kobertz. (2011). Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease. J. Biol. Chem. 286: 28150-28159. 21676880
Campbell, C., F.D.M. Faleel, M.W. Scheyer, S. Haralu, P.L. Williams, W.D. Carbo, A.S. Wilson-Taylor, N.H. Patel, C.R. Sanders, G.A. Lorigan, and I.D. Sahu. (2022). Comparing the structural dynamics of the human KCNE3 in reconstituted micelle and lipid bilayered vesicle environments. Biochim. Biophys. Acta. Biomembr 1864: 183974. 35716725
Chandrasekhar, K.D., T. Bas, and W.R. Kobertz. (2006). KCNE1 subunits require co-assembly with K+ channels for efficient trafficking and cell surface expression. J. Biol. Chem. 281: 40015-40023. 17065152
Coetzee, W.A., Y. Amalillo, J. Chiu, A. Chow, D. Lau, T. McCormack, H. Moreno, M.S. Nadal, A. Ozaita, D. Pountney, M. Saganich, E. Vega-Saenz de Miera, and B. Rudy (1999). Molecular diversity of K+ channels. Ann. N.Y. Acad. Sci USA 868: 233-285. 10414301
Coey, A.T., I.D. Sahu, T.S. Gunasekera, K.R. Troxel, J.M. Hawn, M.S. Swartz, M.R. Wickenheiser, R.J. Reid, R.C. Welch, C.G. Vanoye, C. Kang, C.R. Sanders, and G.A. Lorigan. (2011). Reconstitution of KCNE1 into lipid bilayers: comparing the structural, dynamic, and activity differences in micelle and vesicle environments. Biochemistry 50: 10851-10859. 22085289
David, J.P., J.I. Stas, N. Schmitt, and E. Bocksteins. (2015). Auxiliary KCNE subunits modulate both homotetrameric Kv2.1 and heterotetrameric Kv2.1/Kv6.4 channels. Sci Rep 5: 12813. 26242757
Doi, K., T. Sato, T. Kuramasu, H. Hibino, T. Kitahara, A. Horii, N. Matsushiro, Y. Fuse, and T. Kubo. (2005). Ménière''s disease is associated with single nucleotide polymorphisms in the human potassium channel genes, KCNE1 and KCNE3. ORL J Otorhinolaryngol Relat Spec 67: 289-293. 16374062
Eldstrom, J. and D. Fedida. (2011). The voltage-gated channel accessory protein KCNE2: multiple ion channel partners, multiple ways to long QT syndrome. Expert Rev Mol Med 13: e38. 22166675
Fenyves, B.G., A. Arnold, V.G. Gharat, C. Haab, K. Tishinov, F. Peter, D. de Quervain, A. Papassotiropoulos, and A. Stetak. (2020). Dual Role of an mps-2/KCNE-Dependent Pathway in Long-Term Memory and Age-Dependent Memory Decline. Curr. Biol. [Epub: Ahead of Print] 33259792
Haworth, A.S. and W.J. Brackenbury. (2019). Emerging roles for multifunctional ion channel auxiliary subunits in cancer. Cell Calcium 80: 125-140. [Epub: Ahead of Print] 31071485
Heitzmann, D., V. Koren, M. Wagner, C. Sterner, M. Reichold, I. Tegtmeier, T. Volk, and R. Warth. (2007). KCNE beta subunits determine pH sensitivity of KCNQ1 potassium channels. Cell Physiol Biochem 19: 21-32. 17310097
Honoré, E., B. Attali, G. Romey, C. Heurteaux, P. Ricard, F. Lesage, M. Lazdunski, and J. Barhanin. (1991). Cloning, expression, pharmacology and regulation of a delayed rectifier K+ channel in mouse heart. EMBO. J. 10: 2805-2811. 1655403
Kroncke, B.M., W.D. Van Horn, J. Smith, C. Kang, R.C. Welch, Y. Song, D.P. Nannemann, K.C. Taylor, N.J. Sisco, A.L. George, Jr, J. Meiler, C.G. Vanoye, and C.R. Sanders. (2016). Structural basis for KCNE3 modulation of potassium recycling in epithelia. Sci Adv 2: e1501228. 27626070
Kuenze, G., C.G. Vanoye, R.R. Desai, S. Adusumilli, K.R. Brewer, H. Woods, E.F. McDonald, C.R. Sanders, A.L. George, Jr, and J. Meiler. (2020). Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation. Elife 9:. 33095155
Law, C.L. and C.R. Sanders. (2019). NMR resonance assignments and secondary structure of a mutant form of the human KCNE1 channel accessory protein that exhibits KCNE3-like function. Biomol NMR Assign. [Epub: Ahead of Print] 30603955
Lee, S.M., J. Baik, D. Nguyen, V. Nguyen, S. Liu, Z. Hu, and G.W. Abbott. (2017). Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus. FASEB J. [Epub: Ahead of Print] 28280005
Li, P., H. Liu, C. Lai, P. Sun, W. Zeng, F. Wu, L. Zhang, S. Wang, C. Tian, and J. Ding. (2014). Differential Modulations of KCNQ1 by Auxiliary Proteins KCNE1 and KCNE2. Sci Rep 4: 4973. 24827085
Liu L., Hayashi K., Kaneda T., Ino H., Fujino N., Uchiyama K., Konno T., Tsuda T., Kawashiri MA., Ueda K., Higashikata T., Shuai W., Kupershmidt S., Higashida H. and Yamagishi M. (2013). A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome. Heart Rhythm. 10(1):61-7. 23010577
Lundquist, A.L., C.L. Turner, L.Y. Ballester, and A.L. George, Jr. (2006). Expression and transcriptional control of human KCNE genes. Genomics 87: 119-128. 16303284
Lundquist, A.L., L.J. Manderfield, C.G. Vanoye, C.S. Rogers, B.S. Donahue, P.A. Chang, D.C. Drinkwater, K.T. Murray, and A.L. George, Jr. (2005). Expression of multiple KCNE genes in human heart may enable variable modulation of IKs. J Mol. Cell Cardiol 38: 277-287. 15698834
Lvov, A., S.D. Gage, V.M. Berrios, and W.R. Kobertz. (2010). Identification of a protein-protein interaction between KCNE1 and the activation gate machinery of KCNQ1. J Gen Physiol 135: 607-618. 20479109
Mangubat, E.Z., T.-T. Tseng, and E. Jakobsson. (2003). Phylogenetic analyses of potassium channel auxiliary subunits. J. Mol. Microbiol. Biotechnol. (in press). 12867745
Mashanov, G.I., M. Nobles, S.C. Harmer, J.E. Molloy, and A. Tinker. (2010). Direct observation of individual KCNQ1 potassium channels reveals their distinctive diffusive behavior. J. Biol. Chem. 285: 3664-3675. 19940153
McCrossan, Z.A. and G.W. Abbott. (2004). The MinK-related peptides. Neuropharmacology 47: 787-821. 15527815
McCrossan, Z.A., A. Lewis, G. Panaghie, P.N. Jordan, D.J. Christini, D.J. Lerner, and G.W. Abbott. (2003). MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain. J. Neurosci. 23: 8077-8091. 12954870
McCrossan, Z.A., T.K. Roepke, A. Lewis, G. Panaghie, and G.W. Abbott. (2009). Regulation of the Kv2.1 potassium channel by MinK and MiRP1. J. Membr. Biol. 228: 1-14. 19219384
Morin, T.J. and W.R. Kobertz. (2008). Counting membrane-embedded KCNE β-subunits in functioning K+ channel complexes. Proc. Natl. Acad. Sci. USA 105: 1478-1482. 18223154
O'Mahony, F., R. Alzamora, V. Betts, F. LaPaix, D. Carter, M. Irnaten, and B.J. Harvey. (2007). Female gender-specific inhibition of KCNQ1 channels and chloride secretion by 17β-estradiol in rat distal colonic crypts. J. Biol. Chem. 282: 24563-24573. 17556370
Preston, P., L. Wartosch, D. Günzel, M. Fromm, P. Kongsuphol, J. Ousingsawat, K. Kunzelmann, J. Barhanin, R. Warth, and T.J. Jentsch. (2010). Disruption of the K+ channel β-subunit KCNE3 reveals an important role in intestinal and tracheal Cl- transport. J. Biol. Chem. 285: 7165-7175. 20051516
Roepke, T.K., Anantharam, A., Kirchhoff, P., Busque, S.M., Young, J.B., Geibel, J.P., Lerner, D.J., and Abbott, G.W. (2006). The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J. Biol. Chem. 281: 23740-23747. 16754665
Romey, G., B. Attali, C. Chouabe, I. Abitbol, E. Guillemare, J. Barhanin, and M. Lazdunski. (1997). Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity. J. Biol. Chem. 272: 16713-16716. 9201970
Sahu, I.D., A.F. Craig, M.M. Dunagan, K.R. Troxel, R. Zhang, A.G. Meiberg, C.N. Harmon, R.M. McCarrick, B.M. Kroncke, C.R. Sanders, and G.A. Lorigan. (2015). Probing Structural Dynamics and Topology of the KCNE1 Membrane Protein in Lipid Bilayers via Site-Directed Spin Labeling and Electron Paramagnetic Resonance Spectroscopy. Biochemistry 54: 6402-6412. 26418890
Sand, P.G., A. Luettich, T. Kleinjung, G. Hajak, and B. Langguth. (2010). An Examination of KCNE1 Mutations and Common Variants in Chronic Tinnitus. Genes (Basel) 1: 23-37. 24710009
Schroeder, B.C., S. Waldegger, S. Fehr, M. Bleich, R. Warth, R. Greger, and T.J. Jentsch. (2000). A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403: 196-199. 10646604
Strutz-Seebohm, N., M. Pusch, S. Wolf, R. Stoll, D. Tapken, K. Gerwert, B. Attali, and G. Seebohm. (2011). Structural basis of slow activation gating in the cardiac I Ks channel complex. Cell Physiol Biochem 27: 443-452. 21691061
Tai, K.-K., K.-W. Wang, and S.A.N. Goldstein. (1997). MinK potassium channels are heteromultimeric complexes. J. Biol. Chem. 272: 1654-1658. 8999841
Tapper, A.R. and A.L. George, Jr. (2001). Location and orientation of minK within the IKs potassium channel complex. J. Biol. Chem. 276: 38249-38254. 11479291
Wang W., Kim HJ., Lee JH., Wong V., Sihn CR., Lv P., Perez Flores MC., Mousavi-Nik A., Doyle KJ., Xu Y. and Yamoah EN. (2014). Functional significance of K+ channel beta-subunit KCNE3 in auditory neurons. J Biol Chem. 289(24):16802-13. 24727472
Westhoff, M., C.I. Murray, J. Eldstrom, and D. Fedida. (2017). Photo-Cross-Linking of IKs Demonstrates State-Dependent Interactions between KCNE1 and KCNQ1. Biophys. J. 113: 415-425. 28746852
Zheng, R., K. Thompson, E. Obeng-Gyimah, D. Alessi, J. Chen, H. Cheng, and T.V. McDonald. (2010). Analysis of the interactions between the C-terminal cytoplasmic domains of KCNQ1 and KCNE1 channel subunits. Biochem. J. 428: 75-84. 20196769
Zhou, L., C. Köhncke, Z. Hu, T.K. Roepke, and G.W. Abbott. (2019). The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury. FASEB J. fj201802519R. [Epub: Ahead of Print] 31162977