Spanish Ministry of Science, Innovation, and Universities
PID2019-105872GB-I00
Spain
Citation
Journal: Nat Commun / Year: 2022 Title: Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation. Authors: María Teresa Bueno-Carrasco / Jorge Cuéllar / Marte I Flydal / César Santiago / Trond-André Kråkenes / Rune Kleppe / José R López-Blanco / Miguel Marcilla / Knut Teigen / Sara Alvira ...Authors: María Teresa Bueno-Carrasco / Jorge Cuéllar / Marte I Flydal / César Santiago / Trond-André Kråkenes / Rune Kleppe / José R López-Blanco / Miguel Marcilla / Knut Teigen / Sara Alvira / Pablo Chacón / Aurora Martinez / José M Valpuesta / Abstract: Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by ...Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.
History
Deposition
Aug 20, 2021
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Header (metadata) release
Dec 22, 2021
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Map release
Dec 22, 2021
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Update
Feb 2, 2022
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Current status
Feb 2, 2022
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Film or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 13213 / Average electron dose: 30.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
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Image processing
Particle selection
Number selected: 1626575
CTF correction
Software - Name: Gctf (ver. 1.06)
Initial angle assignment
Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.0)
Final 3D classification
Software - Name: RELION (ver. 2.0)
Final angle assignment
Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.0)
Final reconstruction
Resolution.type: BY AUTHOR / Resolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.0) / Number images used: 152128
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