Structural highlights
Disease
[TY3H_HUMAN] Autosomal recessive dopa-responsive dystonia. The disease is caused by mutations affecting the gene represented in this entry. May play a role in the pathogenesis of Parkinson disease (PD). A genome-wide copy number variation analysis has identified a 34 kilobase deletion over the TH gene in a PD patient but not in any controls.[1]
Function
[TY3H_HUMAN] Plays an important role in the physiology of adrenergic neurons.
Publication Abstract from PubMed
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 A from the catalytic domains. Upon DA binding, a 20-residue alpha-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.
Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation.,Bueno-Carrasco MT, Cuellar J, Flydal MI, Santiago C, Krakenes TA, Kleppe R, Lopez-Blanco JR, Marcilla M, Teigen K, Alvira S, Chacon P, Martinez A, Valpuesta JM Nat Commun. 2022 Jan 10;13(1):74. doi: 10.1038/s41467-021-27657-y. PMID:35013193[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bademci G, Edwards TL, Torres AL, Scott WK, Zuchner S, Martin ER, Vance JM, Wang L. A rare novel deletion of the tyrosine hydroxylase gene in Parkinson disease. Hum Mutat. 2010 Oct;31(10):E1767-71. doi: 10.1002/humu.21351. PMID:20809526 doi:http://dx.doi.org/10.1002/humu.21351
- ↑ Bueno-Carrasco MT, Cuellar J, Flydal MI, Santiago C, Krakenes TA, Kleppe R, Lopez-Blanco JR, Marcilla M, Teigen K, Alvira S, Chacon P, Martinez A, Valpuesta JM. Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation. Nat Commun. 2022 Jan 10;13(1):74. doi: 10.1038/s41467-021-27657-y. PMID:35013193 doi:http://dx.doi.org/10.1038/s41467-021-27657-y
