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Anionic lipids unlock the gates of select ion channels in the pacemaker family.

Schmidpeter PAM, Wu D, Rheinberger J, Riegelhaupt PM, Tang H, Robinson CV, Nimigean CM
Nat Struct Mol Biol 29 1092-1100 (2022)
Related entries: 7tj6, 7tkt

Cited: 11 times
EuropePMC logo PMID: 36352139

Abstract

Lipids play important roles in regulating membrane protein function, but the molecular mechanisms used are elusive. Here we investigated how anionic lipids modulate SthK, a bacterial pacemaker channel homolog, and HCN2, whose activity contributes to pacemaking in the heart and brain. Using SthK allowed the reconstitution of purified channels in controlled lipid compositions for functional and structural assays that are not available for the eukaryotic channels. We identified anionic lipids bound tightly to SthK and their exact binding locations and determined that they potentiate channel activity. Cryo-EM structures in the most potentiating lipids revealed an open state and identified a nonannular lipid bound with its headgroup near an intersubunit salt bridge that clamps the intracellular channel gate shut. Breaking this conserved salt bridge abolished lipid modulation in SthK and eukaryotic HCN2 channels, indicating that anionic membrane lipids facilitate channel opening by destabilizing these interactions. Our findings underline the importance of state-dependent protein-lipid interactions.

Reviews - 7tj5 mentioned but not cited (1)

  1. Structural basis of properties, mechanisms, and channelopathy of cyclic nucleotide-gated channels. Hu Z, Yang J. Channels (Austin) 17 2273165 (2023)

Articles - 7tj5 mentioned but not cited (1)

  1. Anionic lipids unlock the gates of select ion channels in the pacemaker family. Schmidpeter PAM, Wu D, Rheinberger J, Riegelhaupt PM, Tang H, Robinson CV, Nimigean CM. Nat Struct Mol Biol 29 1092-1100 (2022)


Reviews citing this publication (1)

  1. Mass spectrometry of intact membrane proteins: shifting towards a more native-like context. Oluwole A, Shutin D, Bolla JR. Essays Biochem 67 201-213 (2023)

Articles citing this publication (8)

  1. Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel. Gao X, Schmidpeter PAM, Berka V, Durham RJ, Fan C, Jayaraman V, Nimigean CM. Nat Commun 13 6919 (2022)
  2. Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels. Elbahnsi A, Cowgill J, Burtscher V, Wedemann L, Zeckey L, Chanda B, Delemotte L. Elife 12 e80303 (2023)
  3. Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel. Hu Z, Zheng X, Yang J. Nat Commun 14 4284 (2023)
  4. Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization. Handlin LJ, Dai G. Nat Commun 14 6595 (2023)
  5. Native Function of the Bacterial Ion Channel SthK in a Sparsely Tethered Lipid Bilayer Membrane Architecture. Andersson J, Kleinheinz D, Ramach U, Kiesenhofer N, Ashenden A, Valtiner M, Holt S, Koeper I, Schmidpeter PAM, Knoll W. J Phys Chem B 127 3641-3650 (2023)
  6. Studying Membrane Protein-Lipid Specificity through Direct Native Mass Spectrometric Analysis from Tunable Proteoliposomes. Panda A, Brown C, Gupta K. J Am Soc Mass Spectrom 34 1917-1927 (2023)
  7. Assessment of Purity, Functionality, Stability, and Lipid Composition of Cyclofos-nAChR-Detergent Complexes from Torpedo californica Using Lipid Matrix and Macroscopic Electrophysiology. Quesada O, González-Nieves JE, Colón J, Maldonado-Hernández R, González-Freire C, Acevedo-Cintrón J, Rosado-Millán ID, Lasalde-Dominicci JA. J Membr Biol 256 271-285 (2023)
  8. Constitutive activation mechanism of a class C GPCR. Shin J, Park J, Jeong J, Lam JH, Qiu X, Wu D, Kim K, Lee JY, Robinson CV, Hyun J, Katritch V, Kim KP, Cho Y. Nat Struct Mol Biol 31 678-687 (2024)


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