Structure and regulation of the CDK5-p25(nck5a) complex.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, COS Cells, Crystallography, X-Ray, Cyclin-Dependent Kinase 5, Cyclin-Dependent Kinases, Humans, Immunoblotting, Models, Molecular, Molecular Sequence Data, Nerve Tissue Proteins, Peptides, Phosphorylation, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Recombinant Proteins, Sequence Alignment
Amino Acid Sequence, Animals, Binding Sites, COS Cells, Crystallography, X-Ray, Cyclin-Dependent Kinase 5, Cyclin-Dependent Kinases, Humans, Immunoblotting, Models, Molecular, Molecular Sequence Data, Nerve Tissue Proteins, Peptides, Phosphorylation, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Recombinant Proteins, Sequence Alignment
Mol. Cell
Date: Sep. 01, 2001
PubMed ID: 11583627
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