Calmodulin is critical for folding of the Kv7.2 calcium responsive domain as the nascent peptide exits the ribosome

Protein co-translational missfolding lead to diseases, such as Alzheimer or Parkinson, but little is known about the role of ancillary proteins. We have demonstrated for the first time that the co-translational folding assistance by calmodulin (CaM) to the KV7.2 channel Calcium Responsive Domain (CRD) is disrupted in epileptogenic encephalopathy.1 The force exerted during the early folding events of the nascent chain can be assessed with single residue resolution. We describe here the force profile of folding of the CRD during translation. We find that CaM, the most important calcium modulator in eukaryotic cells, is required to generate early folding events on this domain at critical places. This investigation provides new insights into how a critical KV7.2 channel domain acquires its final functional conformation during co-translational synthesis.