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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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.
Original language | English |
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Journal | Structure (London, England : 1993) |
Volume | 31 |
Issue number | 6 |
Pages (from-to) | 689-699e6 |
Number of pages | 11 |
ISSN | 0969-2126 |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
Publisher Copyright:
Copyright © 2023 Elsevier Ltd. All rights reserved.
- cryo-EM, protein regulation, protein structure and dynamics, serotonin biosynthesis, solution NMR, Tryptophan hydroxylase
Research areas
ID: 357054334