title: Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation.
abstract: We show that the combination of an intracellular bi-partite calmodulin (CaM)-binding site and a distant assembly region affect how an ion channel is regulated by a membrane lipid. Our data reveal that regulation by phosphatidylinositol(4,5)bisphosphate (PIP2) and stabilization of assembled Kv7.2 subunits by intracellular coiled-coil regions far from the membrane are coupled molecular processes. Live-cell fluorescence energy transfer measurements and direct binding studies indicate that remote coiled-coil formation creates conditions for different CaM interaction modes, each conferring different PIP2 dependency to Kv7.2 channels. Disruption of coiled-coil formation by epilepsy-causing mutation decreases apparent CaM-binding affinity and interrupts CaM influence on PIP2 sensitivity.
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Araitz
authors.initials: A
authors.lastname: Alberdi
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gomis-Perez
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Ganeko
authors.initials: G
authors.lastname: Bernardo-Seisdedos
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Alaimo
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Covadonga
authors.initials: C
authors.lastname: Malo
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Juncal
authors.initials: J
authors.lastname: Aldaregia
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Robles
authors.affiliation: Departament de Farmacología, UPV/EHU, Universidad del País Vasco, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Areso
authors.affiliation: Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, München 81377, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Butz
authors.affiliation: Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, München 81377, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wahl-Schott
authors.affiliation: Unidad de Biofísica, Consejo Superior de Investigaciones Científicas, CSIC, UPV/EHU, Barrio Sarriena s/n, Leioa 48940, Spain alvaro.villarroel@csic.es.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Villarroel
mesh_terms: D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D002147:Calmodulin; D051658:KCNQ2 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate
keywords: Allosteric; Calmodulin; Coiled-coil; Epilepsy; KCNQ; Leucine zipper; M-current; PIP2