title: A novel mechanism for fine-tuning open-state stability in a voltage-gated potassium channel.
abstract: Voltage-gated potassium channels elicit membrane hyperpolarization through voltage-sensor domains that regulate the conductive status of the pore domain. To better understand the inherent basis for the open-closed equilibrium in these channels, we undertook an atomistic scan using synthetic fluorinated derivatives of aromatic residues previously implicated in the gating of Shaker potassium channels. Here we show that stepwise dispersion of the negative electrostatic surface potential of only one site, Phe481, stabilizes the channel open state. Furthermore, these data suggest that this apparent stabilization is the consequence of the amelioration of an inherently repulsive open-state interaction between the partial negative charge on the face of Phe481 and a highly co-evolved acidic side chain, Glu395, and this interaction is potentially modulated through the Tyr485 hydroxyl. We propose that the intrinsic open-state destabilization via aromatic repulsion represents a new mechanism by which ion channels, and likely other proteins, fine-tune conformational equilibria.
authors: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors: Stephan A
authors: SA
authors: Pless
authors: Ana P
authors: AP
authors: Niciforovic
authors: Jason D
authors: JD
authors: Galpin
authors: John-Jose
authors: JJ
authors: Nunez
authors: Harley T
authors: HT
authors: Kurata
authors: Christopher A
authors: CA
authors: Ahern
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism; D054879:Halogenation; D015640:Ion Channel Gating; D007700:Kinetics; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010649:Phenylalanine / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D055672:Static Electricity; D013223:Statistics as Topic; D013499:Surface Properties; D014982:Xenopus laevis
chemical_list: D050505:Mutant Proteins; D024642:Potassium Channels, Voltage-Gated; D018698:Glutamic Acid; D010649:Phenylalanine
references: Biophys J. 2007 Oct 1;93(7):2341-9
references: 17545248
references: Brain. 2005 Aug;128(Pt 8):1847-54
references: 15958509
references: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11352-7
references: 20534430
references: Biophys J. 1994 Feb;66(2 Pt 1):345-54
references: 8161688
references: J Gen Physiol. 2011 May;137(5):455-72
references: 21518834
references: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11896-9
references: 21730186
references: Nature. 2007 Nov 15;450(7168):376-82
references: 18004376
references: J Gen Physiol. 2002 Jun;119(6):521-32
references: 12034760
references: J Gen Physiol. 1994 Feb;103(2):321-62
references: 8189208
references: Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17784-8
references: 19004768
references: J Gen Physiol. 1998 Mar;111(3):421-39
references: 9482709
references: Neuron. 2007 Oct 4;56(1):124-40
references: 17920020
references: J Biol Chem. 2010 Apr 30;285(18):14005-19
references: 20202932
references: Prog Biophys Mol Biol. 2006 Oct;92(2):185-208
references: 16316679
references: Nat Chem. 2010 Jul;2(7):533-8
references: 20571570
references: Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):452-6
references: 7831309
references: J Gen Physiol. 1999 Mar;113(3):389-414
references: 10051516
references: J Gen Physiol. 2008 Dec;132(6):667-80
references: 19029374
references: Cell. 2002 Oct 18;111(2):231-9
references: 12408867
references: Neuron. 2000 Feb;25(2):411-23
references: 10719895
references: J Physiol. 2007 Dec 1;585(Pt 2):325-37
references: 17932138
references: Science. 1996 Jan 12;271(5246):213-6
references: 8539623
references: J Biol Chem. 2011 Jan 7;286(1):717-25
references: 21059661
references: Science. 1996 Jan 12;271(5246):163-8
references: 8539615
references: Biochemistry. 2009 Sep 22;48(37):8842-51
references: 19663503
references: Nature. 2002 May 30;417(6888):523-6
references: 12037560
references: PLoS Biol. 2009 Mar 3;7(3):e47
references: 19260762
references: J Biol Chem. 2008 Aug 29;283(35):24118-27
references: 18550534
references: J Physiol. 2012 Jun 1;590(11):2591-9
references: 22431339
references: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9459-64
references: 10449714
references: Channels (Austin). 2010 Sep-Oct;4(5):422-8
references: 20935453
references: J Gen Physiol. 2002 Nov;120(5):663-76
references: 12407078
references: Physiol Rev. 2005 Oct;85(4):1205-53
references: 16183911
references: FEBS Lett. 1986 Jul 28;203(2):139-43
references: 3089835
references: Biophys J. 2003 Jan;84(1):295-305
references: 12524283
references: J Biol Chem. 2006 May 5;281(18):12858-64
references: 16524878
references: Science. 2012 Apr 13;336(6078):229-33
references: 22499946
references: Science. 1999 Oct 8;286(5438):295-9
references: 10514373
references: Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12088-93
references: 9770444
references: J Gen Physiol. 2006 Sep;128(3):273-82
references: 16908727
references: Nat Struct Biol. 2003 Jan;10(1):59-69
references: 12483203
references: Nature. 2001 Oct 25;413(6858):809-13
references: 11677598
references: Chem Soc Rev. 2008 Jan;37(1):68-83
references: 18197334
references: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5833-8
references: 20231479
references: J Biol Chem. 2002 May 24;277(21):18994-9000
references: 11864984
references: Nature. 1991 Jan 24;349(6307):305-10
references: 1846229
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6644-9
references: 19346472
references: Neuron. 1997 Nov;19(5):1127-40
references: 9390525
references: Neuron. 2006 Nov 22;52(4):623-34
references: 17114047
references: J Gen Physiol. 1999 Aug;114(2):215-42
references: 10435999
references: Methods Enzymol. 1998;293:504-29
references: 9711626
references: Neuroscience. 1999;91(4):1557-64
references: 10391459
references: Nat Chem Biol. 2011 Jul 24;7(9):617-23
references: 21785425
references: Nat Struct Mol Biol. 2012 May 06;19(6):633-41
references: 22562138
references: J Biol Chem. 2000 Feb 25;275(8):5264-9
references: 10681497
references: Nat Rev Drug Discov. 2009 Dec;8(12):982-1001
references: 19949402
references: Nat Commun. 2011 Jun 14;2:351
references: 21673672