Home Life Sciences The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
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The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition

  • Maurice Dellin EMAIL logo , Ina Rohrbeck , Purva Asrani , Julian A. Schreiber , Nadine Ritter , Frank Glorius , Bernhard Wünsch ORCID logo , Thomas Budde ORCID logo , Louisa Temme , Timo Strünker ORCID logo , Birgit Stallmeyer , Frank Tüttelmann ORCID logo , Sven G. Meuth , Marc Spehr , Johann Matschke ORCID logo , Andrea Steinbicker , Christos Gatsogiannis ORCID logo , Raphael Stoll ORCID logo , Nathalie Strutz-Seebohm and Guiscard Seebohm EMAIL logo
Published/Copyright: February 23, 2023
Biological Chemistry
From the journal Biological Chemistry Volume 404 Issue 4

Abstract

The Phosphatidylinositol 3-phosphate 5-kinase Type III PIKfyve is the main source for selectively generated phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a known regulator of membrane protein trafficking. PI(3,5)P2 facilitates the cardiac KCNQ1/KCNE1 channel plasma membrane abundance and therewith increases the macroscopic current amplitude. Functional-physical interaction of PI(3,5)P2 with membrane proteins and its structural impact is not sufficiently understood. This study aimed to identify molecular interaction sites and stimulatory mechanisms of the KCNQ1/KCNE1 channel via the PIKfyve-PI(3,5)P2 axis. Mutational scanning at the intracellular membrane leaflet and nuclear magnetic resonance (NMR) spectroscopy identified two PI(3,5)P2 binding sites, the known PIP2 site PS1 and the newly identified N-terminal α–helix S0 as relevant for functional PIKfyve effects. Cd2+ coordination to engineered cysteines and molecular modeling suggest that repositioning of S0 stabilizes the channel s open state, an effect strictly dependent on parallel binding of PI(3,5)P2 to both sites.

Keywords: electrophysiology; molecular modeling; phosphatidylinositol; phosphoinositides; phospholipid; potassium channels
Corresponding authors: Maurice Dellin, IfGH–Cellular Electrophysiology, Department of Cardiology and Angiology, University Hospital of Münster, Robert-Koch Str. 45, D-48149, Münster, Germany, E-mail: ; and Guiscard Seebohm, IfGH–Cellular Electrophysiology, Department of Cardiology and Angiology, University Hospital of Münster, Robert-Koch Str. 45, D-48149, Münster, Germany; and GRK 2515, Chemical biology of ion channels (Chembion), Westfälische Wilhelms-Universität Münster, Münster, Germany, E-mail:
Maurice Dellin, Ina Rohrbeck, Nathalie Strutz-Seebohm, and Guiscard Seebohm have contributed equally to this work.

Funding source: Medizinische Fakultät, Westfälische Wilhelms-Universität Münster

Award Identifier / Grant number: Medk

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: CRU326

Award Identifier / Grant number: Chembion

Award Identifier / Grant number: FOR 5146

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: Unassigned

Acknowledgments

We thank G. N. Tseng (Virginia Commonwealth University, Richmond, VA) for providing cysteine-free KCNQ1 mutant channel constructs. We thank Anne Humberg for her excellent technical support. The complete set of NMR spectroscopic data was acquired in 2011 during the master thesis of Ina Rohrbeck (formerly Rothenberg).

  1. Author contributions: MD, IR, NR, JAS, JM, NSS, and GS performed experiments; MD, JAS, and GS performed 3D simulations; NSS, BW, TB, SGM, TS, BS, FT, MS, LT, FG, PA, CG, RS, AS and GS contribute to the experimental design; MD, NSS, and GS wrote the manuscript.

  2. Research funding: This work was supported by the Medizinische Fakultät, Westfälische Wilhelms-Universität Münster, graduate schools Chembion and MedK, Münster, Germany, (grant to MD) and by the Deutsche Forschungsgemeinschaft (FOR 5146 to GS and AS). Further support by the German Research Foundation Clinical Research Unit Male Germ Cells: from Genes to Function (DFG CRU326, grants to FT and TS).

  3. Conflict of interest statement: The authors declare to have no conflict interests.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/hsz-2022-0247).

Received: 2022-08-05
Accepted: 2022-12-13
Published Online: 2023-02-23
Published in Print: 2023-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
https://doi.org/10.1515/hsz-2022-0247
Keywords for this article
electrophysiology; molecular modeling; phosphatidylinositol; phosphoinositides; phospholipid; potassium channels

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
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