Activation of calcium/calmodulin regulated kinases

Among numerous protein kinases found in mammalian cell systems there is a d istinct subfamily of serine/threonine kinases that are regulated by calmodu lin or other related activators in a calcium concentration dependent manner . Members of this family are involved in various cellular processes like ce ll proliferation and death, cell motility and metabolic pathways. In this c ontribution we shall review the available structural biology data on five m embers of this kinase family (calcium / calmodulin dependent kinase, twitch in kinase, titin kinase, phosphorylase kinase, myosin light chain kinase). As a common element, all these kinases contain a regulatory tail, which is C-terminal to their catalytic domain. The available 3D structures of two me mbers, the serine/threonine kinases of the giant muscle proteins twitchin a nd titin in the autoinhibited conformation, show how this regulatory tail b locks their active sites. The structures suggest that activation of these k inases requires unblocking the active site from the C-terminal extension an d conformational rearrangement of the active site loops. Small angle scatte ring data for myosin light chain kinase indicate a complete release of the C-terminal extension upon calcium / calmodulin binding. In addition, member s of this family are regulated by diverse add-on mechanisms, including phos phorylation of residues within the activation segment or the P+1 loop as we ll as by additional regulatory subunits. The available structural data lead to the hypothesis of two different activation mechanisms upon binding to c alcium sensitive proteins. In one model, the regulatory tail is entirely re leased ("fall-apart"). The alternative model ("looping-out") proposes a two -anchored release mechanism.