TCDB is operated by the Saier Lab Bioinformatics Group

 

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

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).

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 speculation 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).

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. 

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:

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
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
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
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
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., K. Hayashi, T. Kaneda, H. Ino, N. Fujino, K. Uchiyama, T. Konno, T. Tsuda, M.A. Kawashiri, K. Ueda, T. Higashikata, W. Shuai, S. Kupershmidt, H. Higashida, and M. Yamagishi. (2012). A novel mutation in the transmembrane non-pore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome. Heart Rhythm. [Epub: Ahead of Print] 23010577
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
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. G├╝nzel, 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
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
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., H.J. Kim, J.H. Lee, V. Wong, C.R. Sihn, P. Lv, C.M. Flores, A. Mousavi-Nik, K.J. Doyle, Y. Xu, and E.N. Yamoah. (2014). Functional Significance of K+ Channel β-Subunit KCNE3 in Auditory Neuron.s. J. Biol. Chem. [Epub: Ahead of Print] 24727472
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