Phosphodegronmediated

Phosphodegronmediated refers to protein degradation that is controlled by phosphodegrons, short motifs within a protein that become binding sites for ubiquitin E3 ligases when phosphorylated. This mechanism links phosphorylation signaling to proteasomal turnover, enabling rapid and selective regulation of protein levels in response to cellular cues.

Mechanism and components. In phosphodegron-mediated degradation, a kinase phosphorylates a degron motif, creating a phosphodegron that is recognized by a specific E3 ubiquitin ligase. The ligase, often a kinase-dependent SCF (Skp1-Cullin-F-box) complex or a Cullin-RING ligase with a phospho-binding substrate receptor, ubiquitinates the substrate, tagging it for destruction by the 26S proteasome. Phosphatases can reverse this process, reversing the signal and stabilizing substrates. Key kinase families include cyclin-dependent kinases (CDKs), CK1, and GSK3. Common E3 ligases involved are SCF complexes with F-box proteins such as Skp2 and Fbw7, or the β-TrCP-containing SCF complex that binds phospho-degrons like those in β-catenin.

Notable examples. In mammals, p27Kip1 is degraded when Thr187 is phosphorylated by CDK2, enabling SCFSkp2 recognition. Cyclin E can be targeted by SCFFbw7 after phosphorylation by CDKs and GSK3, contributing to cyclin E turnover. β-Catenin is marked for degradation through sequential phosphorylation by CK1 and GSK3, creating a phosphodegron recognized by SCFβ-TrCP, a central mechanism in Wnt signaling. In yeast, Sic1 undergoes multiple CDK-dependent phosphodegrons that trigger SCFCdc4-mediated degradation to permit S-phase entry.

Significance. Phosphodegron-mediated degradation tightly coordinates cell cycle progression, signaling pathways, and developmental processes. Dysregulation can contribute to oncogenesis and other diseases, making it a focus of research into targeted therapeutics and cellular control mechanisms.