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

Here we define control of UPS access to Tryptophan-2,3-dioxygenase (TDO2), which converts the essential amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert tryptophanemia.

We discovered that a CK2–β-TrCP kinase-E3 ligase cascade generates and recognizes phosphodegrons in TDO2 unless shielded by Trp binding to an exosite. Effects of Trp analogs on CK2–β-TrCP-dependent ubiquitylation indicated the indole, amino, and carboxylate groups collectively protect TDO2. Cryo-EM reveals these moieties organize a Trp-ordered flap that covers the exosite and thereby restricts generation of adjacent phosphodegrons.