Calmodulin acts as a chaperone during co-translational folding of the Kv7.2 channel Calcium Responsive Domain.

In vivo , the majority of nascent protein chains must begin folding during translation in order to obtain their native structure. While the importance of co-translational folding has become increasingly clear, the specific mechanisms underlying the coordination between the ribosome, nascent chain and molecular chaperones are still uncertain. Here, we have constructed a model of the co-translational folding pathway of the calcium responsive domain (CRD) of the human neuronal K V 7.2 human neuronal ion channel, showing that calmodulin (CaM) is crucial. By combining Force Profile Analysis and single-molecule force spectroscopy techniques, we found that CaM, in a calcium-dependent manner, affects early folding events involving three key α-helices in the CRD. In addition, this study suggests that CaM at early stages induces the formation of metastable hairpins, as a part of the co-translational folding pathway. These findings expand on the role of CaM as a key regulator of folding in eukaryotes: not only as an essential cellular signaling protein, but also as a bona fide co-translational molecular chaperone.