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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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, Günther H.J.

In: Structure (London, England : 1993), Vol. 31, No. 6, 2023, p. 689-699e6.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Vedel, IM, Prestel, A, Zhang, Z, Skawinska, NT, Stark, H, Harris, P, Kragelund, BB & Peters, GHJ 2023, 'Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand', Structure (London, England : 1993), vol. 31, no. 6, pp. 689-699e6. https://doi.org/10.1016/j.str.2023.04.004

APA

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 (London, England : 1993), 31(6), 689-699e6. https://doi.org/10.1016/j.str.2023.04.004

Vancouver

Vedel IM, Prestel A, Zhang Z, Skawinska NT, Stark H, Harris P et al. Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand. Structure (London, England : 1993). 2023;31(6):689-699e6. https://doi.org/10.1016/j.str.2023.04.004

Author

Vedel, Ida M. ; Prestel, Andreas ; Zhang, Zhenwei ; Skawinska, Natalia T. ; Stark, Holger ; Harris, Pernille ; Kragelund, Birthe B. ; Peters, Günther H.J. / Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand. In: Structure (London, England : 1993). 2023 ; Vol. 31, No. 6. pp. 689-699e6.

Bibtex

@article{d90733413d8b4daf87a57c8fad5f40ce,

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

abstract = "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.",

keywords = "cryo-EM, protein regulation, protein structure and dynamics, serotonin biosynthesis, solution NMR, Tryptophan hydroxylase",

author = "Vedel, {Ida M.} and Andreas Prestel and Zhenwei Zhang and Skawinska, {Natalia T.} and Holger Stark and Pernille Harris and Kragelund, {Birthe B.} and Peters, {G{\"u}nther H.J.}",

year = "2023",

doi = "10.1016/j.str.2023.04.004",

language = "English",

volume = "31",

pages = "689--699e6",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "6",

}

RIS

TY - JOUR

T1 - Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand

AU - Vedel, Ida M.

AU - Prestel, Andreas

AU - Zhang, Zhenwei

AU - Skawinska, Natalia T.

AU - Stark, Holger

AU - Harris, Pernille

AU - Kragelund, Birthe B.

AU - Peters, Günther H.J.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - cryo-EM

KW - protein regulation

KW - protein structure and dynamics

KW - serotonin biosynthesis

KW - solution NMR

KW - Tryptophan hydroxylase

U2 - 10.1016/j.str.2023.04.004

DO - 10.1016/j.str.2023.04.004

M3 - Journal article

C2 - 37119821

AN - SCOPUS:85160967957

VL - 31

SP - 689-699e6

JO - Structure

JF - Structure

SN - 0969-2126

IS - 6

ER -

ID: 357054334

Department of Biology