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

Autor:	Vedel IM; Department of Chemistry, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark., Prestel A; Department of Biology, University of Copenhagen, Ole Maaløes vej 5, 2200 Copenhagen N, Denmark., Zhang Z; Department of Structural Dynamics, Max Planck Institute for Multidisciplinary Sciences, Am Faßberg 11, 37077 Göttingen, Germany., Skawinska NT; Department of Chemistry, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark., Stark H; Department of Structural Dynamics, Max Planck Institute for Multidisciplinary Sciences, Am Faßberg 11, 37077 Göttingen, Germany., Harris P; Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen Ø, Denmark., Kragelund BB; Department of Biology, University of Copenhagen, Ole Maaløes vej 5, 2200 Copenhagen N, Denmark. Electronic address: bbk@bio.ku.dk., Peters GHJ; Department of Chemistry, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark. Electronic address: ghp@kemi.dtu.dk.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2023 Jun 01; Vol. 31 (6), pp. 689-699.e6. Date of Electronic Publication: 2023 Apr 28.
DOI:	10.1016/j.str.2023.04.004
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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