Structure and regulation of the CDK5-p25(nck5a) complex

CDK5 plays an indispensable role in the central nervous system, and its der egulation is involved in neurodegeneration. We report the crystal structure of a complex between CDK5 and p25, a fragment of the p35 activator. Despit e its partial structural similarity with the cyclins, p25 displays an unpre cedented mechanism for the regulation of a cyclin-dependent kinase. p25 tet hers the unphosphorylated T loop of CDK5 in the active conformation. Residu e Ser159, equivalent to Thr160 on CDK2, contributes to the specificity of t he CDK5-p35 interaction. Its substitution with threonine prevents p35 bindi ng, while the presence of alanine affects neither binding nor kinase activi ty. Finally, we provide evidence that the CDK5-p25 complex employs a distin ct mechanism from the phospho-CDK2-cyclin A complex to establish substrate specificity.