Dataset Information

XL-MS analysis of human tyrosine hydroxylase

ABSTRACT: Tyrosine hydroxylase (TH) is a highly regulated enzyme that catalyses the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines. Mutations and dysfunction in this enzyme lead to DA deficiency and parkinsonisms of different severity. An understanding of TH deficiency at the level of structure and stability has been lacking to date, as only structures of truncated TH forms have been available. Here, we used cryoEM and XL-MS to determine the high-resolution structure of full-length human tetrameric TH in the absence and presence of the end-product and feedback inhibitor DA bound to the active site

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Miguel Marcilla

LAB HEAD: Fernando Corrales

PROVIDER: PXD024519 | Pride | 2021-12-22

REPOSITORIES: Pride

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Publications

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

Bueno-Carrasco María Teresa MT Cuéllar Jorge J Flydal Marte I MI Santiago César C Kråkenes Trond-André TA Kleppe Rune R López-Blanco José R JR Marcilla Miguel M Teigen Knut K Alvira Sara S Chacón Pablo P Martinez Aurora A Valpuesta José M JM

Nature communications 20220110 1

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 bioch ...[more]

PMID: 35013193

Publication: 1/2

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Project description:Action of alcohol on synaptic mRNA in the amygdala of mice Chronic alcohol consumption induces changes in gene expression, causing persistent long-term neuro-adaptations and the remodeling of synaptic structures. These alcohol-induced synaptic changes may rely specifically on the local translation of mRNAs in the synaptic compartments of the cell. We profiled the transcriptome from synaptoneurosomes (SN) and paired total homogenates (TH) of amygdala to analyze the synaptic adaptations induced by chronic voluntary alcohol consumption in mice. In the SN both the number of alcohol-responsive mRNAs and the magnitude of fold-change were greater than in the TH. Accordingly, the SN detected many genes with coordinated patterns of expression producing a highly connected mRNA network in gene co-expression analysis. The greater sensitivity of the SN preparation allowed for improved cell-type specificity analysis, revealing an up-regulation of alcohol-responsive astrocytic and microglial modules that correlated with alcohol consumption. Alcohol was found to induce changes in the SN functionally important biological pathways, including long-term potentiation, long-term potentiation depression, glutamate pathway, neuro-immune, RNA-processing and translational machineries and provided overlap with changes seen in human alcoholic brain. Transposable elements were responsive to alcohol and found in the down-regulated neuronal mRNA module, which may underlie some of the coordinated gene expression changes associated with alcohol. We provide evidence that enrichment of synaptic components reveals a more intricate network of coordinated gene expression. Increased resolution captures the molecular effects of synaptic manipulations and provides an improved technique for identifying therapeutic targets for alcohol abuse. Synaptoneurosomes (SN) and Paired total homogenates (TH) were prepared from the same homogenate. 42 microarrays were used in total for the alcohol-control analysis (8 alcohol treated mice and 13 controls), 21 SN and 21 paired TH. 2 TH (control) samples were found outliers and were removed from the analysis. For the SN vs. TH analysis, the 2 TH samples found outliers were removed with the 2 paired SN samples.

Dataset Information

XL-MS analysis of human tyrosine hydroxylase

Publications

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

Similar Datasets

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