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dc.contributor.authorUrrutia Iñiguez, Janire
dc.contributor.authorAguado Martínez, Alejandra
dc.contributor.authorGomis Pérez, Carolina
dc.contributor.authorMuguruza Montero, Arantza
dc.contributor.authorRodríguez Ballesteros, Oscar
dc.contributor.authorZhang, Jiaren
dc.contributor.authorNúñez Viadero, Eider ORCID
dc.contributor.authorMalo de la Fuente, Covadonga
dc.contributor.authorChung, Hee Jung
dc.contributor.authorLeonardo Liceranzu, Aritz
dc.contributor.authorBergara Jauregui, Aitor
dc.contributor.authorVillarroel Muñoz, Álvaro
dc.identifier.citationBMC Biology 19(1) : (2021) // Article ID 109es_ES
dc.description.abstractBACKGROUND: The amino acid sequence of proteins generally carries all the necessary information for acquisition of native conformations, but the vectorial nature of translation can additionally determine the folding outcome. Such consideration is particularly relevant in human diseases associated to inherited mutations leading to structural instability, aggregation, and degradation. Mutations in the KCNQ2 gene associated with human epilepsy have been suggested to cause misfolding of the encoded Kv7.2 channel. Although the effect on folding of mutations in some domains has been studied, little is known of the way pathogenic variants located in the calcium responsive domain (CRD) affect folding. Here, we explore how a Kv7.2 mutation (W344R) located in helix A of the CRD and associated with hereditary epilepsy interferes with channel function. RESULTS: We report that the epilepsy W344R mutation within the IQ motif of CRD decreases channel function, but contrary to other mutations at this site, it does not impair the interaction with Calmodulin (CaM) in vitro, as monitored by multiple in vitro binding assays. We find negligible impact of the mutation on the structure of the complex by molecular dynamic computations. In silico studies revealed two orientations of the side chain, which are differentially populated by WT and W344R variants. Binding to CaM is impaired when the mutated protein is produced in cellulo but not in vitro, suggesting that this mutation impedes proper folding during translation within the cell by forcing the nascent chain to follow a folding route that leads to a non-native configuration, and thereby generating non-functional ion channels that fail to traffic to proper neuronal compartments. CONCLUSIONS: Our data suggest that the key pathogenic mechanism of Kv7.2 W344R mutation involves the failure to adopt a configuration that can be recognized by CaM in vivo but not in vitroes_ES
dc.description.sponsorshipThe Government of the Autonomous Community of the Basque Country (IT1165-19 and KK-2020/00110) and the Spanish Ministry of Science and Innovation (RTI2018-097839-B-100 to A.V. and FIS2016-76617-P to A.B.) and FEDER funds and the US National Institute of Neurological Disorders (NINDS) and Stroke Research Project Grant (R01NS083402 to H.J.C.) provided financial support for this work. E.N. and A.M-M. are supported by predoctoral contracts from the Basque Government administered by University of the Basque Country. C.M. was supported by the Basque Government through a Basque Excellence Research Centre (BERC) grant administered by Fundación Biofisika Bizkaia (FBB). J.U. was partially supported by BERC funds. O.R.B. was supported by the Basque Government through a BERC grant administered by Donostia International Physics Center. J.Z. and H.J.C. was supported by the NINDS Research Project Grant #R01NS083402 (PI: H.J.C.).es_ES
dc.subjectco-translational foldinges_ES
dc.subjectforce profile analysises_ES
dc.subjectIQ domaines_ES
dc.subjectKCNQ channelses_ES
dc.titleAn Epilepsy-Causing Mutation Leads to Co-Translational Misfolding of the Kv7.2 Channeles_ES
dc.rights.holderThis article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0) and CC0 1.0 Universal (CC0 1.0) Public Domain Dedicationes_ES
dc.rights.holderAtribución 3.0 España*
dc.departamentoesBioquímica y biología moleculares_ES
dc.departamentoesFísica de materialeses_ES
dc.departamentoeuBiokimika eta biologia molekularraes_ES
dc.departamentoeuMaterialen fisikaes_ES

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This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0) and CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Except where otherwise noted, this item's license is described as This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0) and CC0 1.0 Universal (CC0 1.0) Public Domain Dedication