FC0040
Cyclin-dependent kinase inhibitor Sic1  -  Cell division control protein 4 (Cdc4)

Biological function
Cyclin-dependent kinase inhibitor Sic1 interacts with the SCF ubiquitin ligase subunit Cdc4 in yeast. Phosphorylation of Sic1 induces binding to a WD40 domain in Cdc4 leading to ubiquitination and degradation of Sic1. The phosphorylation-dependent degradation of Sic1 in the late G1 phase of the cell cycle enables the development of B-type cyclin–cyclin-dependent kinase activity and the onset of DNA replication.

Structural evidence
It was shown by NMR that multiple phosphorylated sites on Sic1 interact with Cdc4 in dynamic equilibrium with only local ordering around each site. Regardless of phosphorylation status, Sic1 exists in an intrinsically disordered state but is surprisingly compact with transient structure.

Biochemical evidence
It has been demonstrated that the phosphodegrons of Sic1 consist of suboptimal binding motifs for binding to the WD40 domain. Out of 9 motifs 6 has to be phosphorylated for optimal binding, although only one of them can physically interact with the target. Binding via a single, high-affinity site causes aberrant cell-cycle.

Structure/Mechanism
Phosphorylation in Sic1 serves as an on/off switch and the threshold prohibits premature onset of degradation of Sic1 leads to genome instability. Based on computational results it was proposed that ultra-sensitivity in the Sic1–Cdc4 system may be driven at least in part by cumulative electrostatic interactions.

Mechanism category
tethering

Posttranslational modification
Phosphorylation induces binding to SCF of Cdc4. Phosphorylation however, does not induce ordering. Out of 9 phosphodegrons 6 are required for optimal affinity.

Significance
Fuzziness prohibits premature degradation of Sic1, which could lead to genome instability.

Further reading
17522259, 20399186, 19008353