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NMR solution structure of the N-terminal domain of hERG and its interaction with the S4-S5 linker.

Li Q, Gayen S, Chen AS, Huang Q, Raida M, Kang C
Biochem Biophys Res Commun 403 126-32 (2010)
Cited: 54 times
EuropePMC logo PMID: 21055387

Abstract

The human Ether-à-go-go Related Gene (hERG) potassium channel mediates the rapid delayed rectifier current (IKr) in the cardiac action potential. Mutations in the 135 amino acid residue N-terminal domain (NTD) cause channel dysfunction or mis-translocation. To study the structure of NTD, it was overexpressed and purified from Escherichia coli cells using affinity purification and gel filtration chromatography. The purified protein behaved as a monomer under purification conditions. Far- and near-UV, circular dichroism (CD) and solution nuclear magnetic resonance (NMR) studies showed that the purified protein was well-folded. The solution structure of NTD was obtained and the N-terminal residues 13-23 forming an amphipathic helix which may be important for the protein-protein or protein-membrane interactions. NMR titration experiment also demonstrated that residues from 88 to 94 in NTD are important for the molecular interaction with the peptide derived from the S4-S5 linker.

Reviews - 2l4r mentioned but not cited (2)

  1. HERG potassium channel regulation by the N-terminal eag domain. Gustina AS, Trudeau MC. Cell. Signal. 24 1592-1598 (2012)
  2. The EAG Voltage-Dependent K+ Channel Subfamily: Similarities and Differences in Structural Organization and Gating. Barros F, de la Peña P, Domínguez P, Sierra LM, Pardo LA. Front Pharmacol 11 411 (2020)

Articles - 2l4r mentioned but not cited (1)

  1. The structural mechanism of KCNH-channel regulation by the eag domain. Haitin Y, Carlson AE, Zagotta WN. Nature 501 444-448 (2013)


Reviews citing this publication (7)

  1. hERG K(+) channels: structure, function, and clinical significance. Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. Physiol. Rev. 92 1393-1478 (2012)
  2. The enigmatic cytoplasmic regions of KCNH channels. Morais-Cabral JH, Robertson GA. J. Mol. Biol. 427 67-76 (2015)
  3. Getting to the heart of hERG K(+) channel gating. Perry MD, Ng CA, Mann SA, Sadrieh A, Imtiaz M, Hill AP, Vandenberg JI. J. Physiol. (Lond.) 593 2575-2585 (2015)
  4. Insights into hERG K+ channel structure and function from NMR studies. Ng CA, Torres AM, Pagès G, Kuchel PW, Vandenberg JI. Eur. Biophys. J. 42 71-79 (2013)
  5. Development of Safe Drugs: The hERG Challenge. Kalyaanamoorthy S, Barakat KH. Med Res Rev 38 525-555 (2018)
  6. Atomistic Insights of Calmodulin Gating of Complete Ion Channels. Núñez E, Muguruza-Montero A, Villarroel A. Int J Mol Sci 21 (2020)
  7. Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation. Shi YP, Thouta S, Claydon TW. Front Pharmacol 11 139 (2020)

Articles citing this publication (44)

  1. Structure of the carboxy-terminal region of a KCNH channel. Brelidze TI, Carlson AE, Sankaran B, Zagotta WN. Nature 481 530-533 (2012)
  2. hERG potassium channel gating is mediated by N- and C-terminal region interactions. Gustina AS, Trudeau MC. J. Gen. Physiol. 137 315-325 (2011)
  3. Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. Anderson CL, Kuzmicki CE, Childs RR, Hintz CJ, Delisle BP, January CT. Nat Commun 5 5535 (2014)
  4. Demonstration of physical proximity between the N terminus and the S4-S5 linker of the human ether-a-go-go-related gene (hERG) potassium channel. de la Peña P, Alonso-Ron C, Machín A, Fernández-Trillo J, Carretero L, Domínguez P, Barros F. J. Biol. Chem. 286 19065-19075 (2011)
  5. Direct interaction of eag domains and cyclic nucleotide-binding homology domains regulate deactivation gating in hERG channels. Gianulis EC, Liu Q, Trudeau MC. J. Gen. Physiol. 142 351-366 (2013)
  6. NMR analysis of a novel enzymatically active unlinked dengue NS2B-NS3 protease complex. Kim YM, Gayen S, Kang C, Joy J, Huang Q, Chen AS, Wee JL, Ang MJ, Lim HA, Hung AW, Li R, Noble CG, Lee le T, Yip A, Wang QY, Chia CS, Hill J, Shi PY, Keller TH. J. Biol. Chem. 288 12891-12900 (2013)
  7. Voltage-sensing domain mode shift is coupled to the activation gate by the N-terminal tail of hERG channels. Tan PS, Perry MD, Ng CA, Vandenberg JI, Hill AP. J. Gen. Physiol. 140 293-306 (2012)
  8. Cytoplasmic domains and voltage-dependent potassium channel gating. Barros F, Domínguez P, de la Peña P. Front Pharmacol 3 49 (2012)
  9. The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating. Ng CA, Perry MD, Tan PS, Hill AP, Kuchel PW, Vandenberg JI. PLoS ONE 7 e31640 (2012)
  10. Voltage-dependent gating of HERG potassium channels. Cheng YM, Claydon TW. Front Pharmacol 3 83 (2012)
  11. The eag domain regulates hERG channel inactivation gating via a direct interaction. Gustina AS, Trudeau MC. J. Gen. Physiol. 141 229-241 (2013)
  12. Structural properties of PAS domains from the KCNH potassium channels. Adaixo R, Harley CA, Castro-Rodrigues AF, Morais-Cabral JH. PLoS ONE 8 e59265 (2013)
  13. Molecular determinants of interactions between the N-terminal domain and the transmembrane core that modulate hERG K+ channel gating. Fernández-Trillo J, Barros F, Machín A, Carretero L, Domínguez P, de la Peña P. PLoS ONE 6 e24674 (2011)
  14. Multiple interactions between cytoplasmic domains regulate slow deactivation of Kv11.1 channels. Ng CA, Phan K, Hill AP, Vandenberg JI, Perry MD. J. Biol. Chem. 289 25822-25832 (2014)
  15. Mapping of interactions between the N- and C-termini and the channel core in HERG K+ channels. de la Peña P, Machín A, Fernández-Trillo J, Domínguez P, Barros F. Biochem. J. 451 463-474 (2013)
  16. Trafficking defects in PAS domain mutant Kv11.1 channels: roles of reduced domain stability and altered domain-domain interactions. Ke Y, Ng CA, Hunter MJ, Mann SA, Heide J, Hill AP, Vandenberg JI. Biochem. J. 454 69-77 (2013)
  17. hERG1a N-terminal eag domain-containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: a possible mechanism for long QT syndrome. Trudeau MC, Leung LM, Roti ER, Robertson GA. J. Gen. Physiol. 138 581-592 (2011)
  18. An NMR study of the N-terminal domain of wild-type hERG and a T65P trafficking deficient hERG mutant. Gayen S, Li Q, Chen AS, Nguyen TH, Huang Q, Hill J, Kang C. Proteins 79 2557-2565 (2011)
  19. Expression, purification, and initial structural characterization of nonstructural protein 2B, an integral membrane protein of Dengue-2 virus, in detergent micelles. Huang Q, Chen AS, Li Q, Kang C. Protein Expr. Purif. 80 169-175 (2011)
  20. Concerted all-or-none subunit interactions mediate slow deactivation of human ether-à-go-go-related gene K+ channels. Thomson SJ, Hansen A, Sanguinetti MC. J. Biol. Chem. 289 23428-23436 (2014)
  21. Interactions between the N-terminal tail and the gating machinery of hERG K⁺ channels both in closed and open/inactive states. de la Peña P, Machín A, Fernández-Trillo J, Domínguez P, Barros F. Pflugers Arch. 467 1747-1756 (2015)
  22. Regional flexibility in the S4-S5 linker regulates hERG channel closed-state stabilization. Hull CM, Sokolov S, Van Slyke AC, Claydon TW. Pflugers Arch. 466 1911-1919 (2014)
  23. Solution structure of the PAS domain of a thermophilic YybT protein homolog reveals a potential ligand-binding site. Tan E, Rao F, Pasunooti S, Pham TH, Soehano I, Turner MS, Liew CW, Lescar J, Pervushin K, Liang ZX. J. Biol. Chem. 288 11949-11959 (2013)
  24. The solution structure of the S4-S5 linker of the hERG potassium channel. Gayen S, Li Q, Kang C. J. Pept. Sci. 18 140-145 (2012)
  25. Domain-domain interactions in ion channels. Zheng J. J. Gen. Physiol. 142 347-350 (2013)
  26. Insight into the molecular interaction between the cyclic nucleotide-binding homology domain and the eag domain of the hERG channel. Li Q, Ng HQ, Yoon HS, Kang C. FEBS Lett. 588 2782-2788 (2014)
  27. Role of the cytoplasmic N-terminal Cap and Per-Arnt-Sim (PAS) domain in trafficking and stabilization of Kv11.1 channels. Ke Y, Hunter MJ, Ng CA, Perry MD, Vandenberg JI. J. Biol. Chem. 289 13782-13791 (2014)
  28. An NMR investigation of the structure, function and role of the hERG channel selectivity filter in the long QT syndrome. Gravel AE, Arnold AA, Dufourc EJ, Marcotte I. Biochim. Biophys. Acta 1828 1494-1502 (2013)
  29. Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain. Harley CA, Starek G, Jones DK, Fernandes AS, Robertson GA, Morais-Cabral JH. Proc. Natl. Acad. Sci. U.S.A. 113 9916-9921 (2016)
  30. Calmodulin Regulates Human Ether à Go-Go 1 (hEAG1) Potassium Channels through Interactions of the Eag Domain with the Cyclic Nucleotide Binding Homology Domain. Lörinczi E, Helliwell M, Finch A, Stansfeld PJ, Davies NW, Mahaut-Smith M, Muskett FW, Mitcheson JS. J. Biol. Chem. 291 17907-17918 (2016)
  31. Expression and purification of the p75 neurotrophin receptor transmembrane domain using a ketosteroid isomerase tag. Li Q, Chen AS, Gayen S, Kang C. Microb. Cell Fact. 11 45 (2012)
  32. Structural insight into the transmembrane segments 3 and 4 of the hERG potassium channel. Li Q, Wong YL, Ng HQ, Gayen S, Kang C. J. Pept. Sci. 20 935-944 (2014)
  33. Structure of the Cyclic Nucleotide-Binding Homology Domain of the hERG Channel and Its Insight into Type 2 Long QT Syndrome. Li Y, Ng HQ, Li Q, Kang C. Sci Rep 6 23712 (2016)
  34. Purification and structural characterization of the voltage-sensor domain of the hERG potassium channel. Ng HQ, Kim YM, Huang Q, Gayen S, Yildiz AA, Yoon HS, Sinner EK, Kang C. Protein Expr. Purif. 86 98-104 (2012)
  35. The Eag domain regulates the voltage-dependent inactivation of rat Eag1 K+ channels. Lin TF, Jow GM, Fang HY, Fu SJ, Wu HH, Chiu MM, Jeng CJ. PLoS ONE 9 e110423 (2014)
  36. Conservation analysis of residues in the S4-S5 linker and the terminal part of the S5-P-S6 pore modulus in Kv and HCN channels: flexible determinants for the electromechanical coupling. Balleza D, Carrillo E, Gómez-Lagunas F. Pflugers Arch. 467 2069-2079 (2015)
  37. Ginsenoside Rg3, a Gating Modifier of EAG Family K+ Channels. Wu W, Gardner A, Sachse FB, Sanguinetti MC. Mol. Pharmacol. 90 469-482 (2016)
  38. ¹H, ¹³C and ¹⁵N chemical shift assignments for an intracellular proteinase inhibitor of Bacillus subtilis. Li Q, Chen AS, Gayen S, Kang C. Biomol NMR Assign 7 129-132 (2013)
  39. (1)H, (13)C and (15)N chemical shift assignments for the cyclic-nucleotide binding homology domain of a KCNH channel. Li Q, Ng HQ, Kang C. Biomol NMR Assign 9 55-58 (2015)
  40. Binding interface of cardiac potassium channel proteins identified by hydrogen deuterium exchange of synthetic peptides. Chen J, Angeletti R, McDonald TV, Xiao H. Anal Bioanal Chem 403 1303-1309 (2012)
  41. Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate. Zangerl-Plessl EM, Wu W, Sanguinetti MC, Stary-Weinzinger A. Front Mol Biosci 10 1137368 (2023)
  42. C-Linker Accounts for Differential Sensitivity of ERG1 and ERG2 K+ Channels to RPR260243-Induced Slow Deactivation. Gardner A, Sanguinetti MC. Mol. Pharmacol. 88 19-28 (2015)
  43. L51P, a novel mutation in the PAS domain of hERG channel, confers long QT syndrome by impairing channel activation. Wang M, Gao M, Fang S, Zheng R, Peng D, Luo Q, Yu B. Am J Transl Res 12 8040-8049 (2020)
  44. ¹H, ¹³C and ¹⁵N chemical shift assignments for the N-terminal PAS domain of the KCNH channel from zebrafish. Kim YM, Li Q, Ng HQ, Yoon HS, Kang C. Biomol NMR Assign 8 165-168 (2014)


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