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Bidirectional Allosteric Coupling between PIP2 Binding and the Pore of the Oncochannel TRPV6.
Humer, Christina; Radiskovic, Tamara; Horváti, Kata; Lindinger, Sonja; Groschner, Klaus; Romanin, Christoph; Höglinger, Carmen.
Afiliación
  • Humer C; Institute of Biophysics, Johannes Kepler University Linz, 4020 Linz, Austria.
  • Radiskovic T; Institute of Biophysics, Johannes Kepler University Linz, 4020 Linz, Austria.
  • Horváti K; Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, 1117 Budapest, Hungary.
  • Lindinger S; Institute of Biophysics, Johannes Kepler University Linz, 4020 Linz, Austria.
  • Groschner K; Gottfried Schatz Research Center, Division of Biophysics, Medical University of Graz, 8010 Graz, Austria.
  • Romanin C; Institute of Biophysics, Johannes Kepler University Linz, 4020 Linz, Austria.
  • Höglinger C; Institute of Biophysics, Johannes Kepler University Linz, 4020 Linz, Austria.
Int J Mol Sci ; 25(1)2024 Jan 03.
Article en En | MEDLINE | ID: mdl-38203789
ABSTRACT
The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP2). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there is a compelling need for its pharmacological targeting. Structural studies provide insights on how TRPV6 is affected by different inhibitors, with some binding to sites else occupied by lipids. These include the small molecule cis-22a, which, however, also binds to and thereby blocks the pore. By combining calcium imaging, electrophysiology and optogenetics, we identified residues within the pore and the lipid binding site that are relevant for regulation by cis-22a and PIP2 in a bidirectional manner. Yet, mutation of the cytosolic pore exit reduced inhibition by cis-22a but preserved sensitivity to PIP2 depletion. Our data underscore allosteric communication between the lipid binding site and the pore and vice versa for most sites along the pore.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositoles / Calcio / Canales Catiónicos TRPV Tipo de estudio: Prognostic_studies Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositoles / Calcio / Canales Catiónicos TRPV Tipo de estudio: Prognostic_studies Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Suiza