Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation

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 () and José M. Valpuesta ()
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María Teresa Bueno-Carrasco: Centro Nacional de Biotecnología (CNB-CSIC)
Jorge Cuéllar: Centro Nacional de Biotecnología (CNB-CSIC)
Marte I. Flydal: University of Bergen
César Santiago: Centro Nacional de Biotecnología (CNB-CSIC)
Trond-André Kråkenes: University of Bergen
Rune Kleppe: Haukeland University Hospital
José R. López-Blanco: Instituto de Química Física Rocasolano (IQFR-CSIC)
Miguel Marcilla: Centro Nacional de Biotecnología (CNB-CSIC)
Knut Teigen: University of Bergen
Sara Alvira: Centro Nacional de Biotecnología (CNB-CSIC)
Pablo Chacón: Instituto de Química Física Rocasolano (IQFR-CSIC)
Aurora Martinez: University of Bergen
José M. Valpuesta: Centro Nacional de Biotecnología (CNB-CSIC)

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41467-021-27657-y

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