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

  title={Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation},
  author={M. Teresa Bueno-Carrasco and Jorge Cu{\'e}llar and Marte Innselset Flydal and C{\'e}sar Santiago and Trond-Andr{\'e} Kr{\aa}kenes and Rune Kleppe and Jos{\'e} Ram{\'o}n L{\'o}pez-Blanco and Miguel Marcilla and Knut Erik Teigen and Sara Alvira and Pablo Chac{\'o}n and Aurora Mart{\'i}nez and Jos{\'e} Mar{\'i}a Valpuesta},
  journal={Nature Communications},
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… 
1 Citations


Tyrosine hydroxylase and regulation of dopamine synthesis.
Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for transport along microtubules
It is reported that THSer(P)-31 co-distributes with the Golgi complex and synaptic-like vesicles in rat and human dopaminergic cells and indicates that Ser-31 phosphorylation may regulate TH subcellular localization by enabling its transport along microtubules, notably toward the projection terminals.
Effects of phosphorylation on binding of catecholamines to tyrosine hydroxylase: specificity and thermodynamics.
A structural model for the effect of phosphorylation is proposed and the results show that in the case of binding of dihydroxyphenylalanine, the decrease in affinity upon phosphorylations is due primarily to a decrease in the enthalpy of the interaction.
Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines
Investigation of the role of the N-terminus of TH enzyme in the regulation of both the catalytic activity and the intracellular stability will extend the spectrum of the gene-therapy approach for PD.
Tyrosine hydroxylase phosphorylation in vivo
This review on TH phosphorylation in vivo has three main sections focusing on: the methods used to investigate TH phosphate levels in vivo, the animals used, the sacrifice procedures, the tissue preparation, the measurement of TH protein levels and THosphorylation and the measurements of TH activation.
Identification by hydrogen/deuterium exchange of structural changes in tyrosine hydroxylase associated with regulation.
The effects of dopamine binding and phosphorylation of Ser40 on the kinetics of deuterium incorporation into peptide bonds were examined by mass spectrometry and results are consistent with tyrosine hydroxylase existing in two different conformations.
Crystal structure of tyrosine hydroxylase at 2.3 Å and its implications for inherited neurodegenerative diseases
The structure provides a rationale for the effect of point mutations in TyrOH that cause L-DOPA responsive parkinsonism and Segawa's syndrome.
Differential Regulation of the Human Tyrosine Hydroxylase Isoforms via Hierarchical Phosphorylation*
H hierarchical phosphorylation provides a mechanism whereby the two major human TH isoforms can be differentially regulated with only isoform 1 responding to the ERK pathway, whereas isoform 2 is more sensitive to calcium-mediated events.
Catalytic domain surface residues mediating catecholamine inhibition in tyrosine hydroxylase.
Pure dimeric TH was generated and shown to be the core regulatory unit of TH for CA inhibition, possessing both high and low affinity CA binding sites, indicating that there is symmetry between dimers of the tetramer.