Novel functions of Calmodulin in Kv7.2 regulation and co-translational folding

Resumen

CaM binds to the calcium responsive domain (CRD) of voltage-gated potassium channel 7.2 (Kv7.2), transmitting calcium signaling to control its pore gating. In addition, CaM affects other functions, such as trafficking to the membrane and regulation of the stability of the distal tetramerization domain. In this dissertation, novel roles of CaM in Kv7.2 function are described, such as its involvement in redox regulation and in co-translational folding have been found. On the one hand, CaM regulates the function of Kv7.2 channel via a non-canonical interaction between the non-helical S2S3 linker and EF3 hand loop. This is critical for redox regulation. By acting through the CRD coupled to the S6 gate and through the voltage-sensing domain, CaM can influence gating in two opposing directions simultaneously. In addition, it has been found that CaM assists during co-translational folding of the Kv7.2 CRD in a calcium dependent manner. Thus, the recognition mechanism to the Kv7.2 occurs during co-translational folding, and provably involves a combination of conformational selection and induced fit mechanisms. // CaM binds to the calcium responsive domain (CRD) of voltage-gated potassium channel 7.2 (Kv7.2), transmitting calcium signaling to control its pore gating. In addition, CaM affects other functions, such as trafficking to the membrane and regulation of the stability of the distal tetramerization domain. In this dissertation, novel roles of CaM in Kv7.2 function are described, such as its involvement in redox regulation and in co-translational folding have been found. On the one hand, CaM regulates the function of Kv7.2 channel via a non-canonical interaction between the non-helical S2S3 linker and EF3 hand loop. This is critical for redox regulation. By acting through the CRD coupled to the S6 gate and through the voltage-sensing domain, CaM can influence gating in two opposing directions simultaneously. In addition, it has been found that CaM assists during co-translational folding of the Kv7.2 CRD in a calcium dependent manner. Thus, the recognition mechanism to the Kv7.2 occurs during co-translational folding, and provably involves a combination of conformational selection and induced fit mechanisms.