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The second PI(3,5)P 2 binding site in the S0 helix of KCNQ1 stabilizes PIP 2 -at the primary PI1 site with potential consequences on intermediate-to-open state transition.
- Source :
-
Biological chemistry [Biol Chem] 2023 Feb 23; Vol. 404 (4), pp. 241-254. Date of Electronic Publication: 2023 Feb 23 (Print Publication: 2023). - Publication Year :
- 2023
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Abstract
- The Phosphatidylinositol 3-phosphate 5-kinase Type III PIKfyve is the main source for selectively generated phosphatidylinositol 3,5-bisphosphate (PI(3,5)P <subscript>2</subscript> ), a known regulator of membrane protein trafficking. PI(3,5)P <subscript>2</subscript> facilitates the cardiac KCNQ1/KCNE1 channel plasma membrane abundance and therewith increases the macroscopic current amplitude. Functional-physical interaction of PI(3,5)P <subscript>2</subscript> 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)P <subscript>2</subscript> axis. Mutational scanning at the intracellular membrane leaflet and nuclear magnetic resonance (NMR) spectroscopy identified two PI(3,5)P <subscript>2</subscript> binding sites, the known PIP <subscript>2</subscript> site PS1 and the newly identified N-terminal α-helix S0 as relevant for functional PIKfyve effects. Cd <superscript>2+</superscript> 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)P <subscript>2</subscript> to both sites.<br /> (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)
Details
- Language :
- English
- ISSN :
- 1437-4315
- Volume :
- 404
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36809224
- Full Text :
- https://doi.org/10.1515/hsz-2022-0247