A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability.

Limiting tryptophan levels trigger degradation of TDO2 via a CK2-β-TrCP kinase-E3 ligase cascade that recognizes phosphodegrons unless shielded by Trp binding.

• Why it matters: Understanding how endogenous ligands regulate ubiquitin-proteasome system decisions is crucial for insights into metabolic control and enzyme stability, which are not well characterized.
• What they did: The study examined human TDO2, using cryo-EM and biochemical assays, to show that Trp binding at an exosite prevents phosphodegron formation and subsequent ubiquitylation, with effects mimicked by Trp analogs.
• The result: Findings reveal that Trp stabilizes TDO2 by protecting it from phosphorylation-dependent degradation, suggesting a mechanism where small molecules directly regulate enzyme stability through conformational shielding.