Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand

Tryptophan hydroxylase 2 (TPH2) catalyzes the rate-limiting step in serotonin biosynthesis in the brain. Consequently, regulation of TPH2 is relevant for serotonin-related diseases, yet the regulatory mechanism of TPH2 is poorly understood and structural and dynamical insights are missing. We use NMR spectroscopy to determine the structure of a 47 N-terminally truncated variant of the regulatory domain (RD) dimer of human TPH2 in complex with L-Phe, and show that L-Phe is the superior RD ligand compared with the natural sub-strate, L-Trp. Using cryo-EM, we obtain a low-resolution structure of a similarly truncated variant of the com-plete tetrameric enzyme with dimerized RDs. The cryo-EM two-dimensional (2D) class averages additionally indicate that the RDs are dynamic in the tetramer and likely exist in a monomer-dimer equilibrium. Our results provide structural information on the RD as an isolated domain and in the TPH2 tetramer, which will facilitate future elucidation of TPH2's regulatory mechanism.

Automated summary

The structure and dynamics of Tryptophan hydroxylase 2 (TPH2) and its regulatory mechanism were investigated using NMR spectroscopy and cryo-EM techniques. The results revealed the complexity of TPH2 regulation and the presence of a monomer-dimer equilibrium. These findings provide important insights for understanding the regulatory mechanism of TPH2.