دورية أكاديمية
أعرض في EDS

The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.

التفاصيل البيبلوغرافية
العنوان: The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.
المؤلفون: Kudaibergenova M; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada., Guo J; Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada., Khan HM; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada., Lees-Miller J; Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada., Mousaei M; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada., Miranda W; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada., Ngo VA; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada., Noskov SY; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada., Tieleman DP; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada. Electronic address: tieleman@ucalgary.ca., Duff HJ; Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada. Electronic address: hduff@ucalgary.ca.
المصدر: Biophysical journal [Biophys J] 2022 Dec 06; Vol. 121 (23), pp. 4585-4599. Date of Electronic Publication: 2022 Oct 29.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0370626 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1542-0086 (Electronic) Linking ISSN: 00063495 NLM ISO Abbreviation: Biophys J Subsets: MEDLINE
أسماء مطبوعة: Publication: Cambridge, MA : Cell Press
Original Publication: New York, Published by Rockefeller University Press [etc.] for the Biophysical Society.
مواضيع طبية MeSH: ERG1 Potassium Channel*/chemistry , ERG1 Potassium Channel*/genetics, Humans ; Cations ; Molecular Dynamics Simulation ; Mutation
مستخلص: A cationic leak current known as an "omega current" may arise from mutations of the first charged residue in the S4 of the voltage sensor domains of sodium and potassium voltage-gated channels. The voltage-sensing domains (VSDs) in these mutated channels act as pores allowing nonspecific passage of cations, such as Li + , K + , Cs + , and guanidinium. Interestingly, no omega currents have been previously detected in the nonswapped voltage-gated potassium channels such as the human-ether-a-go-go-related (hERG1), hyperpolarization-activated cyclic nucleotide-gated, and ether-a-go-go channels. In this work, we discovered a novel omega current by mutating the first charged residue of the S4 of the hERG1, K525 to serine. To characterize this omega current, we used various probes, including the hERG1 pore domain blocker, dofetilide, to show that the omega current does not require cation flux via the canonical pore domain. In addition, the omega flux does not cross the conventional selectivity filter. We also show that the mutated channel (K525S hERG1) conducts guanidinium. These data are indicative of the formation of an omega current channel within the VSD. Using molecular dynamics simulations with replica-exchange umbrella sampling simulations of the wild-type hERG1 and the K525S hERG1, we explored the molecular underpinnings governing the cation flow in the VSD of the mutant. We also show that the wild-type hERG1 may form water crevices supported by the biophysical surface accessibility data. Overall, our multidisciplinary study demonstrates that the VSD of hERG1 may act as a cation-selective channel wherein a mutation of the first charged residue in the S4 generates an omega current. Our simulation uncovers the atomistic underpinning of this mechanism.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)
References: Nature. 2007 Mar 1;446(7131):76-8. (PMID: 17330043)
Biophys J. 2015 Mar 24;108(6):1400-1413. (PMID: 25809253)
J Mol Cell Cardiol. 2015 Aug;85:71-8. (PMID: 25986146)
Elife. 2019 Sep 06;8:. (PMID: 31490124)
Science. 2016 Aug 12;353(6300):664-9. (PMID: 27516594)
Biophys J. 1994 Feb;66(2 Pt 1):345-54. (PMID: 8161688)
Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9549-54. (PMID: 10944223)
Cell. 2017 Apr 20;169(3):422-430.e10. (PMID: 28431243)
J Chem Phys. 2013 Oct 28;139(16):164106. (PMID: 24182003)
Eur Biophys J. 2014 Mar;43(2-3):59-69. (PMID: 24362825)
Biophys J. 2010 Nov 3;99(9):2841-52. (PMID: 21044581)
Biophys J. 2012 Mar 21;102(6):1372-82. (PMID: 22455920)
Proc Natl Acad Sci U S A. 1997 May 13;94(10):5456-60. (PMID: 9144259)
Nature. 1991 Oct 24;353(6346):752-6. (PMID: 1944534)
Nat Struct Mol Biol. 2019 Aug;26(8):686-694. (PMID: 31285608)
Biophys J. 2017 Nov 7;113(9):1979-1991. (PMID: 29117522)
Neurology. 1999 Dec 10;53(9):1932-6. (PMID: 10599760)
J Mol Graph. 1996 Feb;14(1):33-8, 27-8. (PMID: 8744570)
J Gen Physiol. 2020 Oct 5;152(10):. (PMID: 32902579)
Biophys J. 2004 Oct;87(4):2365-79. (PMID: 15454436)
Neurology. 2009 May 5;72(18):1544-7. (PMID: 19118277)
Neuron. 1996 Jun;16(6):1169-77. (PMID: 8663993)
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6444-9. (PMID: 21464282)
J Physiol. 2005 Dec 1;569(Pt 2):367-79. (PMID: 16166152)
J Gen Physiol. 2013 Sep;142(3):275-88. (PMID: 23980196)
Neuron. 1996 Jun;16(6):1159-67. (PMID: 8663992)
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19250-5. (PMID: 23134726)
Cell Physiol Biochem. 2008;21(1-3):37-46. (PMID: 18209470)
Mol Pharmacol. 2000 Feb;57(2):367-74. (PMID: 10648647)
J Comput Chem. 2005 Dec;26(16):1781-802. (PMID: 16222654)
J Phys Chem B. 2012 Aug 9;116(31):9424-31. (PMID: 22697583)
Novartis Found Symp. 2005;266:19-35; discussion 35-45. (PMID: 16050260)
Mol Membr Biol. 2009 Dec;26(8):435-47. (PMID: 19878047)
Proc Natl Acad Sci U S A. 2007 May 8;104(19):7904-9. (PMID: 17470814)
J Physiol. 2000 Jul 15;526 Pt 2:265-78. (PMID: 10896755)
Neuron. 2005 Feb 3;45(3):379-88. (PMID: 15694325)
J Chem Phys. 2005 Feb 1;122(5):54101. (PMID: 15740304)
Nat Commun. 2020 Mar 17;11(1):1419. (PMID: 32184399)
Nature. 1996 Feb 29;379(6568):833-6. (PMID: 8587608)
J Physiol. 1997 Jul 1;502 ( Pt 1):45-60. (PMID: 9234196)
J Comput Chem. 2008 Aug;29(11):1859-65. (PMID: 18351591)
Cell. 1998 Nov 25;95(5):649-55. (PMID: 9845367)
Science. 1995 Jul 7;269(5220):92-5. (PMID: 7604285)
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3438-42. (PMID: 8159766)
BMC Bioinformatics. 2006 Jun 22;7:316. (PMID: 16792811)
J Gen Physiol. 2003 Jun;121(6):599-614. (PMID: 12771194)
Biophys J. 2009 Jul 8;97(1):50-8. (PMID: 19580743)
J Gen Physiol. 2010 Aug;136(2):225-36. (PMID: 20660662)
J Membr Biol. 2005 Oct;207(3):169-81. (PMID: 16550488)
J Gen Physiol. 1999 Mar;113(3):415-23. (PMID: 10051517)
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19980-5. (PMID: 19052238)
Neuron. 2005 Jul 21;47(2):183-9. (PMID: 16039561)
Biophys J. 2008 Nov 1;95(9):4205-16. (PMID: 18641071)
J Chem Theory Comput. 2007;3(6):2068-2082. (PMID: 21785577)
Bioinformatics. 2018 Oct 15;34(20):3586-3588. (PMID: 29741570)
Nucleic Acids Res. 2018 Jul 2;46(W1):W363-W367. (PMID: 29860391)
Elife. 2019 Nov 27;8:. (PMID: 31774399)
Mol Pharmacol. 2019 Aug;96(2):259-271. (PMID: 31182542)
J Gen Physiol. 2004 Dec;124(6):703-18. (PMID: 15545400)
J Physiol. 2005 Sep 15;567(Pt 3):737-55. (PMID: 15975984)
J Gen Physiol. 2008 Jun;131(6):549-61. (PMID: 18504314)
Biophys J. 2006 May 15;90(10):3447-68. (PMID: 16500984)
Biophys J. 2021 Feb 16;120(4):738-748. (PMID: 33476597)
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D230-4. (PMID: 14681401)
Q Rev Biophys. 2004 Feb;37(1):15-103. (PMID: 17390604)
J Phys Chem B. 2010 Jun 17;114(23):7830-43. (PMID: 20496934)
J Physiol. 2004 Jul 15;558(Pt 2):417-31. (PMID: 15181157)
J Physiol. 1996 Jun 15;493 ( Pt 3):635-42. (PMID: 8799887)
Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):E5962-E5971. (PMID: 27647906)
Nature. 2004 Feb 5;427(6974):548-53. (PMID: 14765197)
Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10534-9. (PMID: 12928493)
J Gen Physiol. 2013 Sep;142(3):289-303. (PMID: 23980197)
Sci Rep. 2016 Apr 12;6:24182. (PMID: 27067805)
J Gen Physiol. 2000 Jan;115(1):51-8. (PMID: 10613918)
Biophys J. 2010 May 19;98(10):2189-98. (PMID: 20483327)
J Gen Physiol. 2013 Apr;141(4):431-43. (PMID: 23478995)
J Chem Theory Comput. 2021 Mar 9;17(3):1726-1741. (PMID: 33539082)
Nat Methods. 2017 Jan;14(1):71-73. (PMID: 27819658)
J Mol Biol. 2008 Mar 28;377(3):804-18. (PMID: 18280500)
Sci Rep. 2016 Oct 12;6:32536. (PMID: 27731415)
PLoS One. 2010 May 28;5(5):e10876. (PMID: 20526358)
Nat Rev Mol Cell Biol. 2008 Apr;9(4):323-32. (PMID: 18354422)
Channels (Austin). 2010 Mar-Apr;4(2):93-100. (PMID: 20009570)
J Gen Physiol. 2019 Feb 4;151(2):231-246. (PMID: 30530765)
J Gen Physiol. 2007 Jul;130(1):11-20. (PMID: 17591984)
Pharmacol Rev. 2003 Dec;55(4):583-6. (PMID: 14657415)
BMC Neurosci. 2008 Jun 19;9:52. (PMID: 18565223)
معلومات مُعتمدة: R01 GM116961 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Cations)
0 (KCNH2 protein, human)
0 (ERG1 Potassium Channel)
تواريخ الأحداث: Date Created: 20230223 Date Completed: 20230224 Latest Revision: 20240923
رمز التحديث: 20240923
مُعرف محوري في PubMed: PMC9748372
DOI: 10.1016/j.bpj.2022.10.032
PMID: 36815709
قاعدة البيانات: MEDLINE
الوصف
تدمد:1542-0086
DOI:10.1016/j.bpj.2022.10.032