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).