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

• Published in: Nature communications Vol. 13; no. 1; p. 74
• Main Authors: Bueno-Carrasco, María Teresa, Cuéllar, Jorge, Flydal, Marte I., Santiago, César, Kråkenes, Trond-André, Kleppe, Rune, López-Blanco, José R., Marcilla, Miguel, Teigen, Knut, Alvira, Sara, Chacón, Pablo, Martinez, Aurora, Valpuesta, José M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 101/58; 631/378/340; 631/535/1258/1259; 82/16; 82/80; 82/83; Amino Acid Sequence; Biosynthesis; Catalytic Domain; Catecholamine; Catecholamines; Catecholamines - metabolism; Constraining; Cryoelectron Microscopy; Domains; Dopamine; Dopamine - chemistry; Dopamine - metabolism; Dopamine - pharmacology; Egress; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Epinephrine; Homeostasis; Hormones; Humanities and Social Sciences; Humans; Hydroxylase; Models, Molecular; Molecular dynamics; multidisciplinary; Neurotransmitters; Noradrenaline; Norepinephrine; Phosphorylation; Protein Binding; Protein Domains; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - antagonists & inhibitors; Tyrosine 3-Monooxygenase - chemistry; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism
• DOI: 10.1038/s41467-021-27657-y
• ISSN: 2041-1723

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. Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the synthesis of the catecholamine neurotransmitters and hormones dopamine (DA), adrenaline and noradrenaline. Here, the authors present the cryo-EM structures of full-length human TH in the apo form and bound with DA, as well as the structure of Ser40 phosphorylated TH, and discuss the inhibitory and stabilizing effects of DA on TH and its counteraction by Ser40-phosphorylation.