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Eukaryotic cells coordinate the processes of cell growth and division through the activity of cyclin-dependent kinases (Cdks). Cdks generate immense signaling specificity and complexity by modifying hundreds of substrates via reversible phosphorylation. Many Cdk substrates are multiphosphorylated, but the mechanisms underlying the enzymatic activity of Cdks toward such substrates are not fully understood. Cks1 is a small essential protein that physically associates with Cdks, possesses a phosphate-binding pocket, and acts as both a positive and negative regulator of Cdk activity. Cks1 has also been extensively studied for its ability to form domain-swapped homodimers, the formation of which is controlled by two conserved proline residues. This dissertation presents research that combined x-ray crystallography, enzyme kinetics, and biophysical methods to demonstrate a direct role for Cks1 in targeting Cdks to multiphosphorylated substrates and develop a new hypothesis for the conservation of a proline residue that mediates domain-swapping in Cks1.

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