Multiple Phosphorylations Allow Fine-tuning
Sic1 needs to be phosphorylated at multiple sites for ubiquitination-driven degradation (Fig. 2). The multiple phosphorylations are required for Sic1 to be recruited by Cdc4 to the SCF complex. The Cdc4 substrate recognition mechanism includes the interaction with consensus binding motifs on the surface of the folded and phosphorylated Sic1, the so-called Cdc4 phospho-degrons (CPD). It has been shown that the optimal consensus sequence for Cdc4 is a phosphorylated serine or threonine followed by a proline and a basic amino acid. However, none of the CPDs on the surface of the Sic1 show such a composition. Therefore, multiple phosphorylation of Sic1 is necessary to get high-affinity binding to Cdc4. Although this mechanism looks inefficient, it provides advantages for a cell because it is possible to measure the environmental Cln/cdc28 concentration. The number of phosphorylated sites corresponds to the concentration of Cln/cdc28 and Sic1 could be considered as a sensor for this protein. In contrast to the many sharp transitions of ultrasensitive kinase cascade feedback loops, this mechanism allows fine tuned regulation. Moreover, because multiple phosphorylations are required, the probability that Sic1 is degraded by random is small. Using multiple phosphorylation of Sic1, the cell evolved a strategy to highly regulate the onset of DNA replication that is absolutely vital to provide genetic stability.
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