The mysterious behaviour of Sic1

Jeremy Gunawardena


I will discuss a recent paper by Klein et al, which puts forward an unusual explanation for the mysterious behaviour of Sic1. Sic1 is an inhibitor of B-type cyclins that has to be degraded in order for cells to pass through the G1/S transition in the cell cycle. Degradation is initiated by G1 phase cyclins which phosphorylate Sic1 on 9 sites. Phosphorylation results in recognition of Sic1 by the ubiquitin ligase SCF leading to its destruction by the proteasome. Nash et al assert that if 5 or fewer sites are phosphorylated, Sic1 is neither recognised by SCF in-vitro nor degraded in-vivo, while if 6 or more sites are phosphorylated, Sic1 is recognised and rapidly degraded. However, the F-box protein in SCF, which is responsible for substrate recognition, has only 1 phosphopeptide binding domain. How does it manage to count to 6? Klein et al explain this with a kinetic (not thermodynamic) model in which the unstructured nature of Sic1 gives rise to an "effective" binding whose affinity increases exponentially with the number of phosporylated sites.


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