An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel

Janire Urrutia, Alejandra Aguado, Carolina Gomis-Perez, Arantza Muguruza-Montero, Oscar R. Ballesteros, Jiaren Zhang, Eider Nuñez, Covadonga Malo, Hee Jung Chung, Aritz Leonardo, Aitor Bergara, Alvaro Villarroel

Research output: Contribution to journalArticlepeer-review


Background: 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 vitro.

Original languageEnglish (US)
Article number109
JournalBMC biology
Issue number1
StatePublished - Dec 2021


  • Calmodulin
  • Co-translational folding
  • Encephalopathy
  • Epilepsy
  • Force profile analysis
  • IQ domain
  • KCNQ channels

ASJC Scopus subject areas

  • Biotechnology
  • Structural Biology
  • Ecology, Evolution, Behavior and Systematics
  • Physiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • Plant Science
  • Developmental Biology
  • Cell Biology


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