Sic1

Sic1, a protein, is a stoichiometric inhibitor[1] of Cdk1-Clb (B-type cyclins) complexes in the budding yeast Saccharomyces cerevisiae.

[4] Low Cdc28-Clb activity leads to the disassembly of the mitotic spindle, the assembly of the prereplicative complex and initiation of bud formation in yeast.

[4] High Cdc28-Clb levels also initiate DNA replication and duplication of the spindle pole bodies (SPBs).

The stress-activated protein kinase (SAPK) Hog1 phosphorylates Sic1 at a single residue at the carboxyl terminus.

[11] 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.

[8] Although this mechanism looks inefficient, it provides advantages for a cell because it is possible to measure the environmental Cln/cdc28 concentration.

In contrast to the many sharp transitions of ultrasensitive kinase cascade feedback loops, this mechanism allows fine tuned regulation.

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.

Recent studies conducted by Koivomagi et al. have revealed the many intricacies of the multi-phosphorylation reaction between the cyclin-CDK complex and the Sic1 protein.

In addition, the studies also emphasize the influence of other factors on Sic1 phosphorylation, including the Cks1 phospho-binding pocket, cyclin docking motifs, and Cdk1 active site specificity.

All of these mechanisms contribute to the dynamics of the sequence of events leading to Sic1 degradation and initiation of S-phase.

Thus, in Sic1 mutants with one Cdk1 phosphorylation site or only phosphoserines present, Cks1 is unable to properly bind to the substrate and promote Sic1 multi-phosphorylation.

This expansion of the peak phosphorylation range could possibly be attributed to enhanced binding of the priming site to Cks1.

[12][13] Cks1-dependent multi-phosphorylation occurs in a processive or semi-processive manner, evidenced by the lack of intermediate Sic1 phosphorylation states in normal cells.

If its expression is reduced, the result might be unregulated progression from G1 to S-phase which deregulates cell division and simplifies the formation of tumors.

Fig. 1 The diagram shows the role of Sic1 in Clb5,6-Cdk1 inhibition and its phosphorylation-mediated polyubiquitination and destruction. Destruction allows for Clb5,6-Cdk1 activity and S-phase entry.
Fig. 2 The first step of the degradation of Sic1 is its phosphorylation by Cdc28-Cln followed by the degradation through SCF.
Fig. 3 Sic1 protein distinguished by different protein chains. The protein has disordered regions, allowing it to be a useful tool in studying and manipulating phosphorylation sites.
Fig. 4 Sic1 Phosphorylation Mechanism 1. In mechanism 1, Koivomagi proposes that the phosphorylated primary site immediately shifts over to another location so that another CDK site can be phosphorylated during the same binding event.
Fig. 5 Sic1 Phosphorylation Mechanism 2. Koivomagi proposes that phosphorylated primary site does not dissociate from the complex so that the intermediate CDK sites are sequentially phosphorylated in a single binding event.