A team of the Max-Planck Research Unit Enzymology of Protein Folding from Halle in cooperation with research teams of the Harvard University (Boston) and the University of Texas (Houston) shed light on the regulation of the cell cycle. Their findings appear in the Dec. 12. 1997 issue of Science and the results are expected to have considerable implications in the understanding of the mechanism of cell division.
The eukaryotic cell cycle is characterized by defined periods of preparation for chromosome replication (G1), DNA replication (S), preparation for mitosis (G2), and mitosis (M). Proper transition between these states require an evolutionarily highly conserved set of proline directed protein kinases. The overall principle underlying cell cycle regulation is the appropriately timed structural modification of proteins through kinase and phosphatase mediated phosphorylation/ dephosphorylation, and protein degradation.
The new results of the research teams suggest regulation of mitotic progression via a novel mechanism involving binding of a specialized protein (a so called peptidyl-prolyl cis/trans isomerase) to phosphorylated mitotic proteins and catalyzing a conformational change of these binding partners thereby allowing the correct exit from mitosis. The authors were able to show that this catalysis is extremely efficient and that the recognition of the binding partners is sequence- specific and extraordinary dependent on phosphorylation of the target sequences. This consensus binding specificity has been shown to correctly predict some novel isomerase targets. Surprisingly, the target sequences are overlapping with antigens recognized by a known mitosis-specific monoclonal antibody. Moreover, the unique substrate specificity of the essential mitotic isomerase has been rationalized based on the crystal structure and confirmed by mutational analysis.
In summary, the identification of an essential isomerase that both negatively regulates entry into mitosis and is required for proper progression through mitosis provided new insights with respect to the general design of drugs arresting cell in mitosis. This novel drug target might be important for the development of anti-cancer agents.
Journal
Science