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

Autor: Bueno-Carrasco MT; Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain., Cuéllar J; Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain. jcuellar@cnb.csic.es., Flydal MI; Department of Biomedicine, University of Bergen, Bergen, Norway., Santiago C; Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain., Kråkenes TA; Department of Biomedicine, University of Bergen, Bergen, Norway., Kleppe R; Norwegian Centre for Maritime and Diving Medicine, Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway., López-Blanco JR; Instituto de Química Física Rocasolano (IQFR-CSIC), Madrid, Spain., Marcilla M; Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain., Teigen K; Department of Biomedicine, University of Bergen, Bergen, Norway., Alvira S; Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.; School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK., Chacón P; Instituto de Química Física Rocasolano (IQFR-CSIC), Madrid, Spain., Martinez A; Department of Biomedicine, University of Bergen, Bergen, Norway. Aurora.Martinez@uib.no., Valpuesta JM; Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain. jmv@cnb.csic.es.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jan 10; Vol. 13 (1), pp. 74. Date of Electronic Publication: 2022 Jan 10.
DOI: 10.1038/s41467-021-27657-y
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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