Structure and Regulation of the CDK5-p25nck5a Complex

Abstract

CDK5 plays an indispensable role in the central nervous system, and its deregulation is involved in neurodegeneration. We report the crystal structure of a complex between CDK5 and p25, a fragment of the p35 activator. Despite its partial structural similarity with the cyclins, p25 displays an unprecedented mechanism for the regulation of a cyclin-dependent kinase. p25 tethers the unphosphorylated T loop of CDK5 in the active conformation. Residue Ser159, equivalent to Thr160 on CDK2, contributes to the specificity of the CDK5-p35 interaction. Its substitution with threonine prevents p35 binding, while the presence of alanine affects neither binding nor kinase activity. Finally, we provide evidence that the CDK5-p25 complex employs a distinct mechanism from the phospho-CDK2-cyclin A complex to establish substrate specificity.

Structure of the Mediator Subunit Cyclin C and its Implications for CDK8 Function

“…36 The cyclin C residue E91 could alternatively help determine CDK8 substrate specificity, similar to a conserved glutamate in an activator protein of CDK5. 37 …”

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

“…35 Suspension cultures of Sf9 insect cells were grown to a density of 10 6 cells per mL at 28°C and infected with the 2 recombinant baculoviruses at varying multiplicities of infection to identify the most suitable ratios. Cells were harvested 72 h postinfection by centrifugation at 123 g for 10 min and washed in phosphatebuffered saline.…”

Orphan kinases turn eccentric

“…Three-dimensional structures are available for many CDK monomers (CDKs 2, 4, 5, 8 and 9) as well as cyclin/CDK dimers (cyclins A, B, C, H, T and p25/Pho80 in complex with their CDKs), [36][37][38][39][40][41][42] which provided a molecular understanding of how cyclins activate CDKs. 24,43,44 Like all kinases, cyclin-dependent kinases have a two-lobed structure.…”