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Cks and Speedy Confer Specificity to Cyclin-dependent kinase

  • Author(s): McGrath, Denise Ann
  • Advisor(s): Rubin, Seth M
  • et al.
Abstract

Inappropriate cell division and aberrant cell cycles are the hallmarks of cancer. Cyclin dependent kinases (CDKs) are the master regulators of the cell cycle. CDK activity drives cells to divide and suppression of CDK activity inhibits cell division. It is crucial to understand mechanisms of CDK regulation, as many cancers are correlated with inactivating mutations to CDK inhibitors and upregulation of CDK activators. This dissertation presents research that utilizes X-ray crystallography, kinetic assays, and various biochemical and biophysical methods to examine two different aspects of CDK regulation. The first aspect focuses on the small protein called Cyclin-dependent kinases regulatory subunit (Cks). We’ve shown that Cks confers specificity to CDK toward substrates via a phosphate-binding pocket. This specificity is required for multi-site phosphorylation of these substrates as well as in vivo viability. The second aspect investigates the mechanism of CDK activation by the atypical cyclin-like protein Speedy A. Using kinetic assays and X-ray crystallography we have elucidated the molecular source of CDK activation by Speedy. The structure shown shows how Speedy is a potent CDK activator whose expression overrides normal inhibitory cell cycle signaling. These findings reveal the molecular source of CDK regulation by Cks and Spy1 proteins and can inform the development of these proteins as prognostic markers for cancers and design of design of cancer therapeutics.

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