Cyclin-dependent kinase 5–p25 complex (CDK5–p25 complex)

Cyclin-dependent kinase 5–p25 complex is an **aberrant enzyme complex** formed when calpain cleaves the neuronal activator p35, generating p25, which binds and hyperactivates CDK5 in neurons. Unlike physiological CDK5–p35 complexes, CDK5–p25 causes prolonged and deregulated CDK5 activity that alters substrate specificity, disrupts neuronal signaling, and drives neurodegenerative processes. Elevated CDK5–p25 activity is linked to neurodegenerative diseases such as Alzheimer’s and Huntington’s, promoting neuronal cell cycle re-entry, DNA damage, and cell death. Therapeutic strategies seek to inhibit CDK5–p25 formation or activity, for example with small peptide inhibitors (Cdk5i), aiming to restore normal neuronal function and slow disease progression. CDK5–p25 is structurally distinct from other cyclin/Cdk complexes; p25 tethers the CDK5 activation loop, locking the kinase in its active conformation and driving pathological signaling. Deregulation of this complex is a central feature in the molecular pathogenesis of several neurodegenerative disorders.

Other names

CDK5/p25 complexCdk5–p25Cdk5–p25(nck5a)

Inhibition of CDK5/p25 kinase activity by blocking substrate phosphorylation; Disruption of CDK5/p25 complex formation, preventing prolonged aberrant activation