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Structure of the Shaker Kv channel and mechanism of slow C-type inactivation.
<div class='caption-title'>Structure of the Shaker-IR Kv channel in lipid nanodisc.</div>
<div class='caption-title'>Structure of the external pore of wild-type Shaker-IR and the W434F mutant.</div>
Tan XF, Bae C, Stix R, Fernández-Mariño AI, Huffer K, Chang TH, Jiang J, Faraldo-Gómez JD, Swartz KJ
OpenAccess logo Sci Adv 8 eabm7814 (2022)
Cited: 34 times
EuropePMC logo PMID: 35302848

Abstract

Voltage-activated potassium (Kv) channels open upon membrane depolarization and proceed to spontaneously inactivate. Inactivation controls neuronal firing rates and serves as a form of short-term memory and is implicated in various human neurological disorders. Here, we use high-resolution cryo-electron microscopy and computer simulations to determine one of the molecular mechanisms underlying this physiologically crucial process. Structures of the activated Shaker Kv channel and of its W434F mutant in lipid bilayers demonstrate that C-type inactivation entails the dilation of the ion selectivity filter and the repositioning of neighboring residues known to be functionally critical. Microsecond-scale molecular dynamics trajectories confirm that these changes inhibit rapid ion permeation through the channel. This long-sought breakthrough establishes how eukaryotic K+ channels self-regulate their functional state through the plasticity of their selectivity filters.

Reviews - 7sj1 mentioned but not cited (2)

  1. Structure of the voltage-gated potassium channel KV1.3: Insights into the inactivated conformation and binding to therapeutic leads. Chandy KG, Sanches K, Norton RS. Channels (Austin) 17 2253104 (2023)
  2. Mechanisms Underlying C-type Inactivation in Kv Channels: Lessons From Structures of Human Kv1.3 and Fly Shaker-IR Channels. Ong ST, Tyagi A, Chandy KG, Bhushan S. Front Pharmacol 13 924289 (2022)

Articles - 7sj1 mentioned but not cited (5)

  1. Structural basis for C-type inactivation in a Shaker family voltage-gated K+ channel. Reddi R, Matulef K, Riederer EA, Whorton MR, Valiyaveetil FI. Sci Adv 8 eabm8804 (2022)
  2. Early Steps in C-Type Inactivation of the hERG Potassium Channel. Pettini F, Domene C, Furini S. J Chem Inf Model 63 251-258 (2023)
  3. Mutations within the selectivity filter reveal that Kv1 channels have distinct propensities to slow inactivate. Wu X, Gupta K, Swartz KJ. J Gen Physiol 154 e202213222 (2022)
  4. Eukaryotic Kv channel Shaker inactivates through selectivity filter dilation rather than collapse. Stix R, Tan XF, Bae C, Fernández-Mariño AI, Swartz KJ, Faraldo-Gómez JD. Sci Adv 9 eadj5539 (2023)
  5. When Is a Potassium Channel Not a Potassium Channel? Accili E. Function (Oxf) 3 zqac052 (2022)


Reviews citing this publication (2)

  1. Ionic channels in nerve membranes, 50 years on. Hille B. Prog Biophys Mol Biol 169-170 12-20 (2022)
  2. Dilation of ion selectivity filters in cation channels. Huffer K, Tan XF, Fernández-Mariño AI, Dhingra S, Swartz KJ. Trends Biochem Sci 49 417-430 (2024)

Articles citing this publication (25)

  1. Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators. Selvakumar P, Fernández-Mariño AI, Khanra N, He C, Paquette AJ, Wang B, Huang R, Smider VV, Rice WJ, Swartz KJ, Meyerson JR. Nat Commun 13 3854 (2022)
  2. Voltage-sensor movements in the Eag Kv channel under an applied electric field. Mandala VS, MacKinnon R. Proc Natl Acad Sci U S A 119 e2214151119 (2022)
  3. Activation and closed-state inactivation mechanisms of the human voltage-gated KV4 channel complexes. Ye W, Zhao H, Dai Y, Wang Y, Lo YH, Jan LY, Lee CH. Mol Cell 82 2427-2442.e4 (2022)
  4. Cannabidiol sensitizes TRPV2 channels to activation by 2-APB. Gochman A, Tan XF, Bae C, Chen H, Swartz KJ, Jara-Oseguera A. Elife 12 e86166 (2023)
  5. State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels. Park YC, Reddy B, Bavi N, Perozo E, Faraldo-Gómez JD. Elife 12 e81445 (2023)
  6. Interactions between selectivity filter and pore helix control filter gating in the MthK channel. Kopec W, Thomson AS, de Groot BL, Rothberg BS. J Gen Physiol 155 e202213166 (2023)
  7. Structural Basis for pH-gating of the K+ channel TWIK1 at the selectivity filter. Turney TS, Li V, Brohawn SG. Nat Commun 13 3232 (2022)
  8. Mechanisms of ion selectivity and throughput in the mitochondrial calcium uniporter. Delgado BD, Long SB. Sci Adv 8 eade1516 (2022)
  9. Inactivation of the Kv2.1 channel through electromechanical coupling. Fernández-Mariño AI, Tan XF, Bae C, Huffer K, Jiang J, Swartz KJ. Nature 622 410-417 (2023)
  10. Mechanism of external K+ sensitivity of KCNQ1 channels. Abrahamyan A, Eldstrom J, Sahakyan H, Karagulyan N, Mkrtchyan L, Karapetyan T, Sargsyan E, Kneussel M, Nazaryan K, Schwarz JR, Fedida D, Vardanyan V. J Gen Physiol 155 e202213205 (2023)
  11. The nonconducting W434F mutant adopts upon membrane depolarization an inactivated-like state that differs from wild-type Shaker-IR potassium channels. Coonen L, Martinez-Morales E, Van De Sande DV, Snyders DJ, Cortes DM, Cuello LG, Labro AJ. Sci Adv 8 eabn1731 (2022)
  12. Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters. Matamoros M, Ng XW, Brettmann JB, Piston DW, Nichols CG. Nat Commun 14 89 (2023)
  13. Identification of the potassium-binding site in serotonin transporter. Hellsberg E, Boytsov D, Chen Q, Niello M, Freissmuth M, Rudnick G, Zhang YW, Sandtner W, Forrest LR. Proc Natl Acad Sci U S A 121 e2319384121 (2024)
  14. Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels. Chen YT, Hong MR, Zhang XJ, Kostas J, Li Y, Kraus RL, Santarelli VP, Wang D, Gomez-Llorente Y, Brooun A, Strickland C, Soisson SM, Klein DJ, Ginnetti AT, Marino MJ, Stachel SJ, Ishchenko A. Proc Natl Acad Sci U S A 120 e2220029120 (2023)
  15. Honeybee CaV4 has distinct permeation, inactivation, and pharmacology from homologous NaV channels. Bertaud A, Cens T, Chavanieu A, Estaran S, Rousset M, Soussi L, Ménard C, Kadala A, Collet C, Dutertre S, Bois P, Gosselin-Badaroudine P, Thibaud JB, Roussel J, Vignes M, Chahine M, Charnet P. J Gen Physiol 156 e202313509 (2024)
  16. Kv1 channel inactivation: Slow and slower. Short B. J Gen Physiol 154 e202213271 (2022)
  17. Loose Coupling between the Voltage Sensor and the Activation Gate in Mammalian HCN Channels Suggests a Gating Mechanism. Wu X, Cunningham KP, Bruening-Wright A, Pandey S, Larsson HP. Int J Mol Sci 25 4309 (2024)
  18. Molecular rearrangements in S6 during slow inactivation in Shaker-IR potassium channels. Szanto TG, Papp F, Zakany F, Varga Z, Deutsch C, Panyi G. J Gen Physiol 155 e202313352 (2023)
  19. Pentameric assembly of the Kv2.1 tetramerization domain. Xu Z, Khan S, Schnicker NJ, Baker S. Acta Crystallogr D Struct Biol 78 792-802 (2022)
  20. Sensing its own permeant ion: KCNQ1 channel inhibition by external K. Barro-Soria R. J Gen Physiol 155 e202313337 (2023)
  21. Structural Insights and Influence of Terahertz Waves in Midinfrared Region on Kv1.2 Channel Selectivity Filter. Zhao X, Ding W, Wang H, Wang Y, Liu Y, Li Y, Liu C. ACS Omega 9 9702-9713 (2024)
  22. Structural mechanism of voltage-gated sodium channel slow inactivation. Chen H, Xia Z, Dong J, Huang B, Zhang J, Zhou F, Yan R, Shi Y, Gong J, Jiang J, Huang Z, Jiang D. Nat Commun 15 3691 (2024)
  23. Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger. Yeo H, Mehta V, Gulati A, Drew D. Nature 623 193-201 (2023)
  24. Structures of a sperm-specific solute carrier gated by voltage and cAMP. Kalienkova V, Peter MF, Rheinberger J, Paulino C. Nature 623 202-209 (2023)
  25. The binding and mechanism of a positive allosteric modulator of Kv3 channels. Liang Q, Chi G, Cirqueira L, Zhi L, Marasco A, Pilati N, Gunthorpe MJ, Alvaro G, Large CH, Sauer DB, Treptow W, Covarrubias M. Nat Commun 15 2533 (2024)


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