A Single Transmembrane Site in the KCNE-encoded Proteins Controls the Specificity of KvLQT1 Channel Gating

Melman, Yonathan F.; Krumerman, Andrew; McDonald, Thomas V.

doi:10.1074/jbc.m200564200

Cited by 81 publications

(106 citation statements)

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“…MiRP2 is a type 1 transmembrane peptide [Abbott et al, 2001b], and the transmembrane domain is necessary and sufficient for the functional interaction between KCNQ1 and MiRP2; this interaction fixes the S4 segment of KCNQ1 in the active state [Nakajo and Kubo, 2007]. The cytoplasmic domain of MiRP2 has also been suggested to be involved in controlling gating, but probably to a lesser extent than the transmembrane domain [Melman et al, 2002].…”

Section: Brs6-mutations In Kcne3mentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

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Section: Brs6-mutations In Kcne3mentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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“…NIH-PA Author Manuscript NIH-PA Author Manuscript single transmembrane proteins including KCNE1 and minK-related peptides (MiRPs) (9)(10)(11)(12)(13)(14). KCNE1, also known as minK, co-assembles with KCNQ1 in heart muscle cells to form a channel complex that generates the slowly activating cardiac potassium current (I Ks ), an important determinant of myocardial repolarization (9;12;14).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Uniformly-2 H, 13 C, 15 N-labeled KCNE1 was prepared in LMPG micelles at 1.0 mM protein and 4% detergent concentration in a buffer containing 250 mM imidazole, 2 mM EDTA, 2 mM DTT, and 10% D 2 O, pH 6.0. NMR data was collected at 40°C on either a Varian Inova 900 MHz spectrometer with a cryoprobe or a Bruker Avance 600 MHz spectrometer using a conventional probe.…”

Section: Assignment Of Kcne1's Backbone Nmr Resonancesmentioning

confidence: 99%

“…KCNE1 alters several biophysical properties of KCNQ1 channels. The fully-activated whole-cell current is 4−6 times larger when KCNQ1 is complexed with KCNE1, the channel activation rate is reduced by more than an order of magnitude, and activation occurs at more positive potentials (9)(10)(11)(12)(13)(14). The importance of KCNE1 in regulating KCNQ1 channel function is reflected by the fact that a number of inherited mutations in KCNE1 result in long QT syndrome (15)(16)(17)(18), and deafness (19).…”

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confidence: 99%

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Preparation, Functional Characterization, and NMR Studies of Human KCNE1, a Voltage-Gated Potassium Channel Accessory Subunit Associated with Deafness and Long QT Syndrome^,

et al. 2007

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KCNE1, also known as minK, is a member of the KCNE family of membrane proteins that modulate the function of KCNQ1 and certain other voltage-gated potassium channels (K V ). Mutations in human KCNE1 cause congenital deafness and congenital long QT syndrome, an inherited predisposition to potentially life-threatening cardiac arrhythmias. Although its modulation of KCNQ1 function has been extensively characterized, many questions remain regarding KCNE1's structure and location within the channel complex. In this study KCNE1 was overexpressed in E. coli and purified. Micellar solutions of the protein were then microinjected into Xenopus oocytes expressing KCNQ1 channels, followed by electrophysiological recordings to test whether recombinant KCNE1 can co-assemble with the channel. Native-like modulation of channel properties was observed following injection of KCNE1 in lysomyristoylphosphatidylglycerol (LMPG) micelles, indicating that KCNE1 is not irreversibly misfolded and that LMPG is able to act as a vehicle for delivering membrane proteins into the membranes of viable cells. 1 H, 15 N-TROSY NMR experiments indicated that LMPG micelles are well-suited for structural studies of KCNE1, leading to assignment of its backbone resonances and to relaxation studies. The chemical shift data confirmed that KCNE1's secondary structure includes several α-helices and demonstrated that its distal Cterminus is disordered. Surprisingly, for KCNE1 in LMPG micelles there appears to be a break in α-helicity at sites 59−61, near the middle of the transmembrane segment, a feature that is accompanied by increased local backbone mobility. Given that this segment overlaps with sites 57 −59, which are known to play a critical role in modulating KCNQ1 channel activation kinetics, this unusual structural feature is likely of considerable functional relevance.Voltage-gated potassium channels (K V ) play a variety of important roles in human health and disease. For example, human KCNQ1 is essential to the cardiac action potential that mediates heartbeat and is also critical for potassium ion homeostasis in the inner ear(1;2). The function of several K V channels is modulated by accessory proteins including K V channel β subunits (Kvβ)(3-6), potassium channel interacting proteins (KCHiP)(7;8), and the KCNE family of † This study was supported by NIH grant R01 DC007416 to CRS, NIH grant HL077188 to ALG, a Vanderbilt School of Medicine Discovery Grant to CGV, and by a postdoctoral fellowship from the American Heart Association to CT (0625586B). Some data were collected in the SEC NMR facility at the University of Georgia, which is supported by US NIH grant P41 GM066340. The NMR assignments for KCNE1 that are reported in this paper have been deposited in the BMRB with access number 15102. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript single transmembrane proteins including KCNE1 and minK-related peptides (MiRPs) (9)(10)(11)(12)(13)(14). KCNE1, also known as minK, co-assembles with KCNQ1 in heart muscle cells...

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“…38,39 Work on the KCNQ1-KCNE3 channel indicates that KCNE3 probably both interacts with the KCNQ1 pore directly, and also locks open the KCNQ1 voltage-sensing S4 domain, which in turn holds open the pore, and that these actions require residues in the transmembrane and extracellular, juxtamembrane regions of KCNE3. [40][41][42][43][44] However, unlike KCNE3, KCNE2 also provides KCNQ1 with a property essential to its task in parietal cells-enhanced activation with low extracellular pH; in contrast, KCNQ1-KCNE3 channels are pH-insensitive, and homomeric KCNQ1 is inhibited by low pH. 45 Furthermore, in Kcne2-deleted mice, KCNQ1 traffics incorrectly, to the parietal cell basolateral membrane.…”

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confidence: 99%

KCNE2 and the K⁺channel

Abbott

2012

Channels

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Keywords: cardiac arrhythmia, choroid plexus, gastric acid, hypothyroidism, KCNQ1, MiRP1, thyroid KCNE2, originally designated MinK-related peptide 1 (MiRP1), belongs to a five-strong family of potassium channel ancillary (b) subunits that, despite the diminutive size of the family and its members, has loomed large in the field of ion channel physiology. KCNE2 dictates K + channel gating, conductance, a subunit composition, trafficking and pharmacology, and also modifies functional properties of monovalent cationnonselective HCN channels. The Kcne2 2/2 mouse exhibits cardiac arrhythmia and hypertrophy, achlorhydria, gastric neoplasia, hypothyroidism, alopecia, stunted growth and choroid plexus epithelial dysfunction, illustrating the breadth and depth of the influence of KCNE2, mutations which are also associated with human cardiac arrhythmias. Here, the modus operandi and physiological roles of this potent regulator of membrane excitability and ion secretion are reviewed with particular emphasis on the ability of KCNE2 to shape the electrophysiological landscape of both excitable and nonexcitable cells.

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A Single Transmembrane Site in the KCNE-encoded Proteins Controls the Specificity of KvLQT1 Channel Gating

Cited by 81 publications

References 32 publications

The genetic basis of Brugada syndrome: A mutation update

The genetic basis of Brugada syndrome: A mutation update

Preparation, Functional Characterization, and NMR Studies of Human KCNE1, a Voltage-Gated Potassium Channel Accessory Subunit Associated with Deafness and Long QT Syndrome^,

KCNE2 and the K⁺channel

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A Single Transmembrane Site in the KCNE-encoded Proteins Controls the Specificity of KvLQT1 Channel Gating

Cited by 81 publications

References 32 publications

The genetic basis of Brugada syndrome: A mutation update

The genetic basis of Brugada syndrome: A mutation update

Preparation, Functional Characterization, and NMR Studies of Human KCNE1, a Voltage-Gated Potassium Channel Accessory Subunit Associated with Deafness and Long QT Syndrome,

KCNE2 and the K+channel

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Preparation, Functional Characterization, and NMR Studies of Human KCNE1, a Voltage-Gated Potassium Channel Accessory Subunit Associated with Deafness and Long QT Syndrome^,

KCNE2 and the K⁺channel