Chapter 4 : The Molecular Basis of K Channel Gating

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Until recently, electrophysiology served as an indirect window into one's understanding of channel gating and structure. A clearer picture of protein movements involved in gating has recently emerged from the merger of crystallographic and spectroscopic studies with functional analysis. These and other emerging results are discussed from the perspective that understanding the molecular process in details of gating helps explain how a wide variety of effectors can function to open or close a target channel, allowing for the large diversity of channels. A large helix opening may not be a requirement for channel gating as a small helix bend can allow K ions an adequate path for flow. The cytoplasmic gating ring of the channel is formed by an octamer of RCK domains. The mechanism of channel gating lies at the core of one's understanding of how channels respond to specific stimuli. Information extracted from functional, crystallographic, and spectroscopic studies of prokaryotic channels has revealed molecular details of how the inner helices and the selectivity filter are involved in channel gating. Focusing the gating forces at a consistent position along the ion conduction pathway allows channels to exist with a large diversity of regulatory domains but maintain a conserved core architecture necessary for efficient function.

Citation: Ptak C, Liu Y, Perozo E. 2005. The Molecular Basis of K Channel Gating, p 69-81. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch4
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Image of Figure 1.
Figure 1.

Inner helix bending motion. (A) A single inner helix from the four known K channel structures (closed: KcsA, black; KirBac, dark gray; open: MthK, gray; KvAP, white) was aligned from the selectivity filter to the glycine hinge. The opposite KcsA inner helix is shown to provide the relative position of the bending helix within the tetramer. (B) A top view of the separation of inner transmembrane helices. (C) Cα-Cα?distances for residues along the inner helices of K channel structures provide an idea of the size of the ion conduction pathway. Major differences between open and closed channels occur after the glycine hinge.the rigidness of the whole helix has been shown by recent crystal structures to be broken at a glycine hinge point (equivalent to G99 in KcsA). Nevertheless, the specific details of the separation of the inner helices measured by EPR are a good representation of the movements involved in KcsA gating. In a complementary experiment using site-directed mass tagging of pore-lining residues in KcsA, an increase in cysteine residue accessibility to methanethiosulfonate reagents was observed at lower pH values ( ).

Citation: Ptak C, Liu Y, Perozo E. 2005. The Molecular Basis of K Channel Gating, p 69-81. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch4
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Image of Figure 2.
Figure 2.

MthK gating movements. Ligand-induced conformational changes in the cytoplasmic gating ring control the open state of MthK. A structural alignment (MthK-Ca, black; KtnBsu-nad, dark gray; Kch-empty, gray; KtnBsu-nadh, white) of the hinge between the RCK domain and the peripheral domain provides insight into the physical movements within the cytoplasmic domain dimer that occur in response to the release of ligand.

Citation: Ptak C, Liu Y, Perozo E. 2005. The Molecular Basis of K Channel Gating, p 69-81. In Kubalski A, Martinac B (ed), Bacterial Ion Channels and Their Eukaryotic Homologs. ASM Press, Washington, DC. doi: 10.1128/9781555816452.ch4
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1. Anantharaman, V.,, E. V. Koonin,, and L. Aravind. 2001. Regulatory potential, phyletic distribution and evolution of ancient, intracellular small-molecule-binding domains. J. Mol. Biol. 307: 1271 1292.
2. Borbat, P. P.,, H. S. McHaourab,, and J. H. Freed. 2002. Protein structure determination using long-distance constraints from double-quantum coherence ESR: study of T4 lysozyme. J. Am. Chem. Soc. 124: 5304 5314.
3. Cornette, J. L.,, K. B. Cease,, H. Margalit,, J. L. Spouge,, J. A. Berzofsky,, and C. DeLisi. 1987. Hydrophobicity scales and computational techniques for detecting amphipathic structures in proteins. J. Mol. Biol. 195: 659 685.
4. Cortes, D. M.,, L. G. Cuello,, and E. Perozo. 2001. Molecular architecture of full-length KcsA: role of cytoplasmic domains in ion permeation and activation gating. J. Gen. Physiol. 117: 165 180.
5. Cortes, D. M.,, and E. Perozo. 1997. Structural dynamics of the Streptomyces lividans K + channel (SKC1): oligomeric stoichiometry and stability. Biochemistry 36: 10343 10352.
6. Cox, D. H.,, and R. W. Aldrich. 2000. Role of the beta1 subunit in large-conductance Ca 2+-activated K + channel gating energetics. Mechanisms of enhanced Ca 2+ sensitivity. J. Gen. Physiol. 116: 411 432.
7. Cuello, L. G.,, J. G. Romero,, D. M. Cortes,, and E. Perozo. 1998. pH-dependent gating in the Streptomyces lividans K + channel. Biochemistry 37: 3229 3236.
8. Cui, J.,, and R. W. Aldrich. 2000. Allosteric linkage between voltage and Ca 2+-dependent activation of BK-type mslo1 K +channels . Biochemistry 39: 15612 15619.
9. del Camino, D.,, M. Holmgren,, Y. Liu,, and G. Yellen. 2000. Blocker protection in the pore of a voltage-gated K + channel and its structural implications. Nature 403: 321 325.
10. Doyle, D. A.,, J. Morais Cabral,, R. A. Pfuetzner,, A. Kuo,, J. M. Gulbis,, S. L. Cohen,, B. T. Chait,, and R. MacKinnon. 1998. The structure of the potassium channel: molecular basis of K + conduction and selectivity. Science 280: 69 77.
11. Farahbakhsh, Z. T.,, C. Altenbach,, and W. L. Hubbell. 1992. Spin labeled cysteines as sensors for protein-lipid interaction and conformation in rhodopsin. Photochem. Photobiol. 56: 1019 1033.
12. Gibrat, J. F.,, T. Madej,, and S. H. Bryant. 1996. Surprising similarities in structure comparison. Curr. Opin. Struct. Biol. 6: 377 385.
13. Gross, A.,, L. Columbus,, K. Hideg,, C. Altenbach,, and W. L. Hubbell. 1999. Structure of the KcsA potassium channel from Streptomyces lividans: a site-directed spin labeling study of the second transmembrane segment. Biochemistry 38: 10324 10335.
14. Gulbis, J. M.,, and D. A. Doyle. 2004. Potassium channel structures: do they conform? Curr. Opin. Struct. Biol. 14: 440 446.
15. Heginbotham, L.,, L. Kolmakova-Partensky,, and C. Miller. 1998. Functional reconstitution of a prokaryotic K + channel. J. Gen. Physiol. 111: 741 749.
16. Heginbotham, L.,, M. LeMasurier,, L. Kolmakova-Partensky,, and C. Miller. 1999. Single Streptomyces lividans K + channels: functional asymmetries and sidedness of proton activation. J. Gen. Physiol. 114: 551 560.
17. Hellmer, J.,, and C. Zeilinger. 2003. MjK1, a K + channel from M. jannaschii, mediates K + uptake and K + sensitivity in E. coli. FEBS Lett. 547: 165 169.
18. Hilgemann, D. W.,, and R. Ball. 1996. Regulation of cardiac Na +,Ca 2+ exchange and KATP potassium channels by PIP2. Science 273: 956 959.
19. Hilgemann, D. W.,, S. Feng,, and C. Nasuhoglu. 2001. The complex and intriguing lives of PIP 2 with ion channels and transporters. Sci. STKE 2001: RE19.
20. Horrigan, F. T.,, and R. W. Aldrich. 2002. Coupling between voltage sensor activation, Ca 2+ binding and channel opening in large conductance (BK) potassium channels. J. Gen. Physiol. 120: 267 305.
21. Hu, L.,, J. Shi,, Z. Ma,, G. Krishnamoorthy,, F. Sieling,, G. Zhang,, F. T. Horrigan,, and J. Cui. 2003. Participation of the S4 voltage sensor in the Mg 2+-dependent activation of large conductance (BK) K + channels. Proc. Natl. Acad. Sci. USA 100: 10488 10493.
22. Huang, C. L.,, S. Feng,, and D. W. Hilgemann. 1998. Direct activation of inward rectifier potassium channels by PIP 2 and its stabilization by G + . Nature 391: 803 806.
23. Hubbell, W. L.,, A. Gross,, R. Langen,, and M. A. Lietzow. 1998. Recent advances in site-directed spin labeling of proteins. Curr. Opin. Struct. Biol. 8: 649 656.
24. Hung, A. Y.,, and M. Sheng. 2002. PDZ domains: structural modules for protein complex assembly. J. Biol. Chem. 277: 5699 5702.
25. Hustedt, E. J.,, A. I. Smirnov,, C. F. Laub,, C. E. Cobb,, and A. H. Beth. 1997. Molecular distances from dipolar coupled spin-labels: the global analysis of multifrequency continuous wave electron paramagnetic resonance data. Biophys. J. 72: 1861 1877.
26. Im, Y. J.,, J. H. Lee,, S. H. Park,, S. J. Park,, S. H. Rho,, G. B. Kang,, E. Kim,, and S. H. Eom. 2003. Crystal structure of the Shank PDZ-ligand complex reveals a class I PDZ interaction and a novel PDZ-PDZ dimerization. J. Biol. Chem. 278: 48099 48104.
27. Jiang, Y.,, A. Lee,, J. Chen,, M. Cadene,, B. T. Chait,, and R. MacKinnon. 2002. Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417: 515 522.
28. Jiang, Y.,, A. Lee,, J. Chen,, V. Ruta,, M. Cadene,, B. T. Chait,, and R. MacKinnon. 2003a. X-ray structure of a voltage-dependent K + channel. Nature 423: 33 41.
29. Jiang, Y.,, A. Pico,, M. Cadene,, B. T. Chait,, and R. MacKinnon. 2001. Structure of the RCK domain from the E. coli K + channel and demonstration of its presence in the human BK channel. Neuron 29: 593 601.
30. Jiang, Y.,, V. Ruta,, J. Chen,, A. Lee,, and R. MacKinnon. 2003b. The principle of gating charge movement in a voltage-dependent K + channel. Nature 423: 42 48.
31. Jin, T.,, L. Peng,, T. Mirshahi,, T. Rohacs,, K. W. Chan,, R. Sanchez,, and D. E. Logothetis. 2002. The βγsubunits of G proteins gate a K + channel by pivoted bending of a transmembrane segment. Mol. Cell 10: 469 481.
32. Jones, B. E.,, P. Rajagopal,, and R. E. Klevit. 1997. Phosphorylation on histidine is accompanied by localized structural changes in the phosphocarrier protein, HPr from Bacillus subtilis. Protein. Sci. 6: 2107 2119.
33. Kelly, B. L.,, and A. Gross. 2003. Potassium channel gating observed with site-directed mass tagging. Nat. Struct. Biol. 10: 280 284.
Kuo, A.,, J. M. Gulbis,, J. F. Antcliff,, T. Rahman,, E. D. Lowe,, J. Zimmer,, J. Cuthbertson,, F. M. Ashcroft,, T. Ezaki,, and D. A. Doyle. 2003.a. Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300: 1922 1926.
35. Kuo, M. M.,, Y. Saimi,, and C. Kung. 2003b. Gain-of-function mutations indicate that Escherichia coli Kch forms a functional K + conduit in vivo. EMBO J. 22: 4049 4058.
36. Labro, A. J.,, A. L. Raes,, I. Bellens,, N. Ottschytsch,, and D. J. Snyders. 2003. Gating of shaker-type channels requires the flexibility of S6 caused by prolines. J. Biol. Chem. 278: 50724 50731.
37. Liu, Y.,, M. Holmgren,, M. E. Jurman,, and G. Yellen. 1997. Gated access to the pore of a voltage-dependent K + channel. Neuron 19: 175 184.
38. Liu, Y. S.,, P. Sompornpisut,, and E. Perozo. 2001. Structure of the KcsA channel intracellular gate in the open state. Nat. Struct. Biol. 8: 883 887.
39. Magidovich, E.,, and O. Yifrach. 2004. Conserved gating hinge in ligand- and voltage-dependent K + channels. Biochemistry 43: 13242 13247.
40. Magleby, K. L. 2003. Gating mechanism of BK (Slo1) channels: so near, yet so far. J. Gen. Physiol. 121: 81 96.
41. McHaourab, H. S.,, M. A. Lietzow,, K. Hideg,, and W. L. Hubbell. 1996. Motion of spin-labeled side chains in T4 lysozyme. Correlation with protein structure and dynamics. Biochemistry 35: 7692 7704.
42. McHaourab, H. S.,, K. J. Oh,, C. J. Fang,, and W. L. Hubbell. 1997. Conformation of T4 lysozyme in solution. Hinge-bending motion and the substrate-induced conformational transition studied by site-directed spin labeling. Biochemistry 36: 307 316.
43. Molina, M. L.,, J. A. Encinar,, F. N. Barrera,, G. Fernandez-Ballester,, G. Riquelme,, and J. M. Gonzalez-Ros. 2004. Influence of C-terminal protein domains and protein-lipid interactions on tetramerization and stability of the potassium channel KcsA. Biochemistry 43: 14924 14931.
44. Niu, X.,, X. Qian,, and K. L. Magleby. 2004. Linker-gating ring complex as passive spring and Ca 2+-dependent machine for a voltage- and Ca 2+-activated potassium channel. Neuron 42: 745 756.
45. Perozo, E.,, D. M. Cortes,, and L. G. Cuello. 1998. Three-dimensional architecture and gating mechanism of a K + channel studied by EPR spectroscopy. Nat. Struct. Biol. 5: 459 469.
46. Perozo, E.,, D. M. Cortes,, and L. G. Cuello. 1999. Structural rearrangements underlying K +-channel activation gating. Science 285: 73 78.
47. Ptak, C. P.,, L. G. Cuello,, and E. Perozo. 2005. Electrostatic interaction of a K + channel RCK domain with charged membrane surfaces. Biochemistry 44: 62 71.
48. Rabenstein, M. D.,, and Y. K. Shin. 1995. Determination of the distance between two spin labels attached to a macromolecule. Proc. Natl. Acad. Sci. USA 92: 8239 8243.
49. Roosild, T. P.,, S. Miller,, I. R. Booth,, and S. Choe. 2002. A mechanism of regulating transmembrane potassium flux through a ligand-mediated conformational switch. Cell 109: 781 791.
50. Shi, J.,, G. Krishnamoorthy,, Y. Yang,, L. Hu,, N. Chaturvedi,, D. Harilal,, J. Qin,, and J. Cui. 2002. Mechanism of magnesium activation of calcium-activated potassium channels. Nature 418: 876 880.
51. Sompornpisut, P.,, Y.-S. Liu,, and E. Perozo. 2001. Calculation of rigid-body conformational changes using restraint-driven cartesian transformations. Biophys. J. 81: 2530 2546.
52. Waygood, E. B. 1998. The structure and function of HPr. Biochem. Cell Biol. 76: 359 367.
53. Webster, S. M.,, D. Del Camino,, J. P. Dekker,, and G. Yellen. 2004. Intracellular gate opening in Shaker K + channels defined by high-affinity metal bridges. Nature 428: 864 868.
54. Xia, X. M.,, X. Zeng,, and C. J. Lingle. 2002. Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature 418: 880 884.
55. Yi, B. A.,, Y. F. Lin,, Y. N. Jan,, and L. Y. Jan. 2001. Yeast screen for constitutively active mutant G proteinactivated potassium channels. Neuron 29: 657 667.
56. Zhao, Y.,, V. Yarov-Yarovoy,, T. Scheuer,, and W. A. Catterall. 2004. A gating hinge in Na + channels; a molecular switch for electrical signaling. Neuron 41: 859 865.
57. Zhou, Y.,, J. H. Morais-Cabral,, A. Kaufman,, and R. MacKinnon. 2001. Chemistry of ion coordination and hydration revealed by a K + channel-Fab complex at 2.0 A resolution. Nature 414: 43 48.

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