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Date
10/13/2011 13:25:52
Group number
PI name
Peña, P.
Channel family
Kv10-12 (eag family)
Channel name
human ether-a-go-go related gene, hERG, Kv11.1, KCNH2
Channel subunit
UNIPROT
Relevant publication (1)
Warmke & Ganetzky (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci USA 91: 3438.
Relevant publication (2)
Sanguinetti et al (1995) A mechanistic link between an inherited and an adquired cardiac arrhythmia. Cell 81: 299.
Relevant publication (3)
Sanguinetti (2010) HERG1 channelopathies. Pflügers Arch 460: 265.
CD
No information
FTIR
NMR
Pore region (NMR):
Torres et al (2003) Structure of the HERG K+ Channel S5P Extracellular Linker. Role of an amphipathic alpha-helix in C-type inactivation. J Biol Chem 278: 42136.;
Pages et al (2009) Structure of the pore-helix of the hERG K+ channel. Eur Biophys J 39: 111.;
Ju et al (2009) The Pore Domain Outer Helix Contributes to Both Activation and Inactivation of the hERG K+ Channel. J Biol Chem. 284, 1000.
Absorbance /
Fluorescence
Interaction protein (1)
KCNE2 (MiRP1) and KCNE1 (MinK): Um et al (2007) Differential Association between HERG and KCNE1 or KCNE2. PLoS ONE 9, e933.
Interaction protein (2)
Hsp70 and Hsp90: Ficker et al (2003) Role of the Cytosolic Chaperones Hsp70 and Hsp90 in Maturation of the Cardiac Potassium Channel hERG. Circ Res 92, e87.
Interaction protein (3)
FHL2: Lin et al (2008) The four and a half LIM domain protein 2 interacts with and regulates the HERG channel. FEBS J 275: 4531.
Interaction protein (4)
KvLQT1/Kv7.1: Ehrlich et al (2004) KvLQT1 Modulates the Distribution and Biophysical Properties of HERG. A novel beta-subunit interaction between delayed rectifier currents. J Biol Chem 279: 1233.
PDB (1)
N-terminal PAS domain: 1BYW; Morais-Cabral et al (1998) Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95: 649.
PDB (2)
NMR: 2L0W, 2L1M, 2I4R;
Li et al (2010) NMR solution structure of the N-terminal domain of hERG and its interaction with the S4–S5 linker. Biochem Biophys Res Commun 403: 126;
Ng et al (2011) The N-terminal tail of hERG contains an amphipathic alpha-helix that regulates channel deactivation. PLoS ONE 6: e16191.;
Muskett et al (2011) Mechanistic insight into hERG K+ channel deactivation gating from the solution structure of the eag domain. J Biol Chem 286: 6184.
PDB (3)
Expression tissues
Heart, brain and other central nervous system locations, myometrium, pancreas, gut, endocrine system, hematopoietic progenitors, several cancerous cells.
Einarsen et al (2009) Functional properties of human neuronal Kv11 channels. Pflügers Arch 458: 689.;
Larsen (2010) Role of ERG1 isoforms in modulation of ERG1 channel trafficking and function. Pflügers Arch 460: 803.;
Asher et al (2010) Eag and HERG potassium channels as novel therapeutic targets in cancer. World J Surg Oncol 8: 113.
Expression cell lines
Stably transfected cell line HEK293 H36/T1, see: Miranda et al (2005) Specificity of TRH receptor coupling to G-proteins for regulation of ERG K+ channels in GH3 rat anterior pituitary cells. J Physiol 566: 717.
Expression plasmids
pcDNA 3B hERG; Miranda et al (2005) Specificity of TRH receptor coupling to G-proteins for regulation of ERG K+ channels in GH3 rat anterior pituitary cells. J Physiol 566: 717.
Level of expression
Channel quaternary
Tetramer
Agonists
Type III antiarrhythmics, great variety of non-antiarrhytmic compounds.Perrin et al (2008) Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction. Prog Biophys Mol Biol 98: 137.; Perry et al (2010) Revealing the structural basis of action of hERG potassium channel activators and blockers. J Physiol 588: 3157.
Smile agonist
Antagonists and blockers
Smile antagonist
Structure-function
relationship
Vandenberg et al (2004) The HERG K+ channel: progress in understanding the molecular basis of its unusual gating kinetics. Eur Biophys J 33: 89.
Van Slyke et al (2010) Mutations within the S4–S5 Linker Alter Voltage Sensor Constraints in hERG K+ Channels. Biophys J 99: 2841.
Ng et al (2011) The N-terminal tail of hERG contains an amphipathic alpha-helix that regulates channel deactivation. PLoS ONE 6: e16191.
Perrin et al (2008) Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction. Prog Biophys Mol Biol 98: 137.
Molecular determinant assembly
Phartiyal et al (2007) Heteromeric Assembly of Human Ether-a-go-go-related Gene (hERG) 1a/1b Channels Occurs Cotranslationally via N-terminal Interactions. J Biol Chem 282: 9874.
Phartiyal et al (2008) Endoplasmic Reticulum Retention and Rescue by Heteromeric Assembly Regulate Human ERG 1a/1b Surface Channel Composition. J Biol Chem 286: 3702.
Molecular determinant clustering
de la Peña et al (2011) Demonstration of physical proximity between the amino terminus and the S4–S5 linker of the h-ERG potassium channel. J Biol Chem 286: 19065.
Fernández-Trillo et al (2011) Molecular Determinants of Interactions between the N-Terminal Domain and the Transmembrane Core That Modulate hERG K+ Channel Gating. PLoS ONE 6: e24674.
Molecular determinant trafficking
Phartiyal et al (2007) Heteromeric Assembly of Human Ether-a-go-go-related Gene (hERG) 1a/1b Channels Occurs Cotranslationally via N-terminal Interactions. J Biol Chem 282: 9874.
Phartiyal et al (2008) Endoplasmic Reticulum Retention and Rescue by Heteromeric Assembly Regulate Human ERG 1a/1b Surface Channel Composition. J Biol Chem 286: 3702.
Larsen (2010) Role of ERG1 isoforms in modulation of ERG1 channel trafficking and function. Pflügers Arch 460: 803.
FKBP38: Walker et al (2007) Co-chaperone FKBP38 Promotes HERG Trafficking. J Biol Chem 282: 23509.
Molecular determinant binding
Perrin et al (2008) Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction. Prog Biophys Mol Biol 98: 137.Perry et al (2010) Revealing the structural basis of action of hERG potassium channel activators and blockers. J Physiol 588: 3157.
Mutants constructs
- hERG variant with deletion in the N-terminus: Δ2-370

- hERG variants with deletions in the eag/PAS domain of the N-terminus:
Δ2-16 and Δ2-135

- hERG variants with deletions in the proximal domain of the N-terminus:
Δ138-373
Δ223-373
Δ284-373
Δ326-373
Δ333-373
Δ346-373
Δ355-373
Δ363-373

- hERG variants with internal modifications and deletions (or insertions) in the proximal domain of the N-terminus:
Δ155-209
Δ326-341
InsA326-341
InsB326-341
Δ326-341+ Δ363-373
Δ326-341+ KKR/AAA
YTS/AAA+ Δ363-373
YTS/AAA+KKR/AAA

- hERG variants with internal deletion in the C-terminus:
Δ864-1010

- hERG variants non-inactivating (S620T):
S620T
S620T+Δ2-370
S620T+Δ138-373
S620T+Δ223-373
S620T+Δ355-373

- hERG variants with the HA epitope fused at the N-terminus, in the eag domain and in the extracellular S1-S2 linker:
H3HA hERG
H3HA+S620T hERG
HA BstXI hERG
HA2 BstXI hERG
HAext hERG

- hERG single point mutants in the intracellular S4-S5 linker and variants N-terminally deleted:
D540C
R541H
R541A
Y542C
S543C
E544C
Y545C
G546C
R541A+ Δ2-370
Y542C+Δ2-370
G546C+Δ2-370

Viloria, C.G., Barros, F., Giráldez, T., Gómez-Varela, D., de la Peña, P. (2000). Differential effects of amino-terminal distal and proximal domains in the regulation of human erg K+ channel gating. Biophys. J. 79, 231–246.
Gómez-Varela, D., de la Peña, P., García, J., Giráldez, T., Barros. F. (2002). Influence of amino-terminal structures on kinetic transitions between several closed and open states in human erg K+ channels. J. Membrane Biol. 187, 117–133.
Gómez-Varela, D., Barros, F., Viloria, C.G., Giráldez, T., Manso, D.G., Dupuy, S.G., Miranda, P. and de la Peña, P. (2003). Relevance of the proximal domain in the amino-terminus of HERG channels for regulation by a phospholipase C-coupled hormone receptor. FEBS Lett. 535, 125–130.
Alonso-Ron. C., de la Peña, P., Miranda, P., Domínguez, P., Barros, F. (2008). Thermodynamic and kinetic properties of amino-terminal and S4-S5 loop HERG channel mutants under steady-state conditions. Biophys. J. 94, 3893–3911.
Alonso-Ron, C., Barros, F., Manso, D.G., Gómez-Varela, D., Miranda, P., Carretero, L., Domínguez, P., de la Peña, P. (2009). Participation of HERG channel cytoplasmic structures on regulation by the G protein-coupled TRH receptor. Pflügers Arch. 457, 1237-1252.

- hERG variants fluorescently labeled at N-terminus:
pEYFP-C1-hERG (YFP-1)
pECFP-C1-hERG (CFP-1)

- hERG variants fluorescently labeled at C-terminus:
pEYFP-N1-hERG (YFP/1159)
pECFP-N1-hERG (CFP-1159)

- hERG variants fluorescently labeled at internal positions (only functional constructs):
VFP-144
CFP-162
CFP-195
VFP-213
VFP-219
VFP-231
CFP-237
VFP-251
VFP-264
CFP-329
CFP-345
VFP-345
CFP-905
VFP-905
VFP-936
CFP-1030
VFP-1040
VFP-1065
VFP-1082
CFP-1123
VFP-1123
CFP-1158
VFP-1158

- hERG functional variants double fluorescentlly labeled:
YFP-1/CFP-345
YFP-1/CFP-905
YFP-1/CFP1158
VFP-345/CFP905
VFP-345/CFP1158

Miranda, P., Manso, D.G., Barros, F., Carretero, L., Hughes, T.E., Alonso-Ron, C., Domínguez, P., de la Peña, P. (2008). FRET with multiply labeled HERG K+ channels as a reporter of the in vivo coarse architecture of the cytoplasmic domains. Biochim. Biophys. Acta 1783, 1681-1699.

- hERG point mutants to cysteine in the N-terminus and S4-S5 linker:
P2C
V3C
R4C
R5C
G6C
V8C
P2C+Y542C
V3C+Y542C
R4C+Y542C
R5C+Y542C,
G6C+ Y542C
V8C+Y542C
V3C+ Y545C
V3C+G546C

- hERG point mutants in native cysteine residues
V3C+ C723G-C729G
V3C+ C740G-C750G
V3C+ C39A
V3C+ C44A
V3C+C49A
V3C+C52A
V3C+C64A
V3C+C66A
V3C+C105A
V3C+C108A

De la Peña, P., Alonso-Ron, C., Machín, A., Fernández-Trillo, J., Carretero, L., Domínguez, P., Barros, F. (2011). Demonstration of physical proximity between the amino terminus and the S4-S5 linker of the hERG potassium channel J. Biol. Chem. 286, 19065-19075.

- hERG recombinant eag domains fluorescently labeled at the C-terminus
N1-135/YFP (WT eag)
N1-135/YFP +V3C (V3C eag)
N1-135/YFP +R4C (R4C eag)
N1-135/YFP +G6C (G6C eag)
N1-135/YFP +V8C (V8C eag)

Fernández-Trillo, J., Barros, F., Machín, A., Carretero, L., Domínguez, P., de la Peña, P. (2011). Molecular determinants of interactions between the N-terminal domain and the transmembrane core that modulate hERG K+ channel gating. PLoS ONE 6 (9): e24674.
Antibodies
Anti-Kv11.1
Against 430-445 linker S1-S2. pAb Rabbit. Alomone APC-109HERG (H-15S)
Against 97-270 N-terminus. pAb Rabbit. Santa Cruz SC-20130HERG (C-20)
Against C-terminus. pAb Goat. Santa Cruz SC-15968HERG1 (CT)
Against 1106-1158 C-terminus. pAb Rabbit. ENZO ALX-215-049
Diseases
Type 2 Long-QT syndrome, short-QT syndrome, epilepsy, skeletal muscel atrophy, developmental disorders, cancer.
Sanguinetti (2010) HERG1 channelopathies. Pflügers Arch 460: 265.; Asher et al (2010) Eag and HERG potassium channels as novel therapeutic targets in cancer. World J Surg Oncol 8: 113.

 

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