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

Vedel, Ida M.; Prestel, Andreas; Zhang, Zhenwei; Skawinska, Natalia T.; Stark, Holger; Harris, Pernille; Kragelund, Birthe B.; Peters, Gunther H. J.

doi:10.1016/j.str.2023.04.004

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

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Zhang, Zhenwei
Department of Structural Dynamics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Stark, Holger
Department of Structural Dynamics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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引用

Vedel, I. M., Prestel, A., Zhang, Z., Skawinska, N. T., Stark, H., Harris, P., Kragelund, B. B., & Peters, G. H. J. (2023). Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand. Structure, 31(6), 689-699.e6. doi:10.1016/j.str.2023.04.004.

引用: https://hdl.handle.net/21.11116/0000-000D-B06C-3

要旨

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 substrate, L-Trp. Using cryo-EM, we obtain a low-resolution structure of a similarly truncated variant of the complete 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.