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

DOI: 10.1038/s41467-021-27657-y DOI Help

Authors: Maria Teresa Bueno-Carrasco (Centro Nacional de Biotecnología (CNB-CSIC)) , Jorge Cuellar (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 (University of Bristol; Centro Nacional de Biotecnología (CNB-CSIC)) , Pablo Chacón (Instituto de Química Física Rocasolano (IQFR-CSIC)) , Aurora Martinez (University of Bergen) , José Maria Valpuesta (Centro Nacional de Biotecnología (CNB-CSIC))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 13

State: Published (Approved)
Published: January 2022
Diamond Proposal Number(s): 15997 , 22006

Open Access Open Access

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.

Diamond Keywords: Parkinson’s Disease

Subject Areas: Biology and Bio-materials, Chemistry

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Other Facilities: AU-CD at ASTRID2; CM01 at ESRF

Added On: 17/01/2022 10:36

Documents:
s41467-021-27657-y.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)