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.
Ray Deshaies and James Ferrell, "Multisite phosphorylation and the countdown to S phase", Cell, 107:819-22, 2001 (minireview). PubMed.
James Ferrell, "Six steps to destruction", Nature, 414:514-21, 2001 (comment). PubMed.
Peter Klein, Tony Pawson and Mike Tyers, "Mathematical modelling suggests cooperative interactions between a disordered polyvalent ligand and a single receptor site", Currrent Biology, 13:1669-78, 2003. PubMed.
Piers Nash et al, "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication", Nature, 414:514-21, 2001. PubMed.
Stephen Orlicky et al, "Structural basis for phosphodependent substrate selection and orientation by the SCF(Cdc4) ubiquitin ligase", Cell, 112:243-56, 2003. PubMed.