Activation of latent cyclin‐dependent kinase 5 (Cdk5)–p35 complexes by membrane dissociation

Cyclin‐dependent kinase 5 (Cdk5) is a Ser/Thr kinase of increasingly recognized importance in a large number of fields, ranging from neuronal migration to synaptic plasticity and neurodegeneration. However, little is known about its mechanism of activation beyond its requirement for binding to p35 or p39. We have examined membrane interactions as one method of regulating the Cdk5–p35 complex. The kinase activity of Cdk5–p35 is low when it is bound to membranes. The Cdk5–p35 found in rat brain extract associates with membranes in two ways. Approximately 75% of complexes associate with membranes via ionic interactions only, and the remaining 25% associate with membranes via ionic interactions together with lipidic interactions. Solubilization with detergent or high‐salt solution activates Cdk5–p35 several fold, and this activation is reversible. Therefore, membrane interactions represent a novel mechanism for the regulation of Cdk5–p35 kinase activity.