Structure of a conserved regulator of cyclin-dependent kinase (CDK)
Seth Rubin group (University of California - Santa Cruz)
Structural results of importance to cancer research came
from the group of Seth Rubin at the University of California at Santa Cruz,
who solved the structure of Cks, a conserved regulator of cyclin-dependent
kinase (CDK). Clarifying the underlying mechanisms and cellular contexts of
Cks function is critical because Cks is essential for proper cell growth, and
its overexpression has been linked to cancer. The group observed that
budding-yeast Cks associates with select phosphorylated sequences in
cell-cycle-regulatory proteins. The 2.9-? crystal structure of Cks bound to
a phosphorylated CDK substrate revealed the molecular interactions
responsible for specificity. The structural details motivated the mutational
analysis that demonstrated that Cks enhances CDK activity in response to
phosphorylation of specific priming sites. The structural work was a basis
for characterizing the biochemical function of Cks and provided detailed
molecular insights into an important mechanism of cell cycle regulation.
Figure: Peptide-swapped Cks.
Citation: McGrath, DA, Balog, ERM, K?ivom?gi, M, Lucena, R,
Mai, MV, Hirschi, A, Kellogg, DR, Loog, M, Rubin, SM. Cks confers
specificity to phosphorylation-dependent CDK signaling pathways, Nat. Struct.
Mol. Biol. 20 (12), 1407-1414 (2013). DOI: 10.1038/nsmb.2707