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キーワード:
Cataldo Tarricone5, 1,
Rani Dhavan5, 2,
Junmin Peng2,
Liliana B. Areces1,
Li-Huei Tsai4, 2, 3,
Andrea Musacchio4, 1, Corresponding author contact information
1 Structural Biology Unit, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, I-20141 Milan, Italy
2 Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 USA
3 Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 USA
要旨:
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.
