Divergent
co-evolution of a CDK substrate and its cyclin.
Tsvia Gildor,
Revital Shemer, Daniel Kornitzer
Dept. of Microbiology, Technion Faculty of Medicine, 2, Efron St., Haifa,
31096, Israel (Gildor@tx.technion.ac.il)
Gcn4, a central regulator of the response of S. cerevisiae to amino acid starvation, is regulated at both the levels of translation and of protein stability. Regulated degradation of Gcn4 depends on its phosphorylation on a specific threonine by the cyclin-dependent kinase Pho85, followed by ubiquitination by the SCFCDC4 ubiquitin ligase. Gcn4 phosphorylation requires a specific cyclin, Pcl5; other Pho85 cyclins, such as Pho80, are unable to target Gcn4 for phosphorylation. A functional homolog of Gcn4 was recently described in the related ascomycete C. albicans. Here, we report the isolation of the functional homolog of Pcl5 from C. albicans, and we show that the regulatory loop that includes Gcn4 and Pcl5 is conserved in C. albicans: like in S. cerevisiae, CaPcl5 is transcriptionally induced by CaGcn4, and is required for CaGcn4 degradation. However, there is no cross-recognition between the proteins from the two species: CaGcn4 is only phosphorylated in the presence of CaPcl5, and similarly, ScGcn4 requires ScPcl5 for its phosphorylation, indicating that the cyclin plays a crucial role in substrate recognition. Analysis of the activity of hybrids of different Pho85 cyclins suggests that the cyclin box domain of Pcl5 determines the substrate specificity of the protein.