Structure and regulation of the CDK5-p25nck5a complex

Tarricone, Cataldo; Dhavan, Rani; Peng, Junmin; Areces, Liliana B.; Tsai, Li-Huei; Musacchio, Andrea

doi:10.1016/S1097-2765(01)00343-4

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Structure and regulation of the CDK5-p25^nck5a complex

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Musacchio, Andrea
Abt. I:Mechanistische Zellbiologie, Max Planck Institute of Molecular Physiology, Max Planck Society;

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Citation

Tarricone, C., Dhavan, R., Peng, J., Areces, L. B., Tsai, L.-H., & Musacchio, A. (2001). Structure and regulation of the CDK5-p25^nck5a complex. MOLECULAR CELL, 8(3), 657-669. doi:10.1016/S1097-2765(01)00343-4.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0015-3B1F-3

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.