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-Reference-Cited by-同舟云学术

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

Published:2023-02-23 Issue:4 Volume:404 Page:241-254
ISSN:1431-6730
Container-title:Biological Chemistry
language:en
Short-container-title:

Author:

Dellin Maurice¹,Rohrbeck Ina¹,Asrani Purva²,Schreiber Julian A.¹³,Ritter Nadine¹⁴,Glorius Frank⁴⁵,Wünsch Bernhard³⁴^ORCID,Budde Thomas⁴⁶^ORCID,Temme Louisa³⁴,Strünker Timo⁴⁷⁸^ORCID,Stallmeyer Birgit⁹,Tüttelmann Frank⁹^ORCID,Meuth Sven G.¹⁰,Spehr Marc¹¹,Matschke Johann¹²^ORCID,Steinbicker Andrea¹³,Gatsogiannis Christos¹⁴^ORCID,Stoll Raphael²^ORCID,Strutz-Seebohm Nathalie¹,Seebohm Guiscard¹⁴

Affiliation:

1. IfGH–Cellular Electrophysiology, Department of Cardiology and Angiology , University Hospital of Münster , Robert-Koch Str. 45, D-48149 , Münster , Germany

2. Faculty of Chemistry and Biochemistry, Biomolecular NMR Spectroscopy and RUBiospek|NMR , Ruhr University of Bochum , Universitätsstraße 150, D-44780 , Bochum , Germany

3. Institut für Pharmazeutische und Medizinische Chemie , Westfälische Wilhelms-Universität Münster , Corrensstraße 48, D-48149 , Münster , Germany

4. GRK 2515, Chemical biology of ion channels (Chembion) , Westfälische Wilhelms-Universität Münster , Münster , Germany

5. Organisch-Chemisches Institut , Westfälische Wilhelms-Universität Münster , Corrensstrasse 40, D-48149 , Münster , Germany

6. Institute of Physiology I , Westfälische Wilhelms-Universität , Robert-Koch-Str. 27a, D-48149 , Münster , Germany

7. Centre of Reproductive Medicine and Andrology , University Hospital Münster, University of Münster , Domagkstraße 11, D-48149, Münster , Germany

8. Cells in Motion Interfaculty Centre , University of Münster , Münster , Germany

9. Institute of Reproductive Genetics , University of Münster , Vesaliusweg 12-14, D-48149 , Münster , Germany

10. Department of Neurology , Heinrich Heine University Düsseldorf , Moorenstraße 5, D-40225 , Düsseldorf , Germany

11. Department of Chemosensation , Institute for Biology II, RWTH Aachen University , Worringerweg 3, D-52074, Aachen , Germany

12. Institute of Cell Biology (Cancer Research) , University Hospital Essen, University of Duisburg-Essen , D-45147 , Essen , Germany

13. Goethe University Frankfurt and University Hospital Frankfurt , Theodor-Stern-Kai 7, D-60590 , Frankfurt , Germany

14. Institute for Medical Physics and Biophysics and Center for Soft Nanoscience , Westfälische Wilhelms-Universität Münster , Münster , Busso-Peus Strasse 10, D-48149 , Germany

Abstract

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.

Funder

Medizinische Fakultät, Westfälische Wilhelms-Universität Münster

Deutsche Forschungsgemeinschaft

Publisher

Walter de Gruyter GmbH

Subject

Clinical Biochemistry,Molecular Biology,Biochemistry

Link

https://www.degruyter.com/document/doi/10.1515/hsz-2022-0247/pdf

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