title: Regulation of tyrosine hydroxylase is preserved across different homo- and heterodimeric 14-3-3 proteins.
abstract: Tyrosine hydroxylase (TH) is regulated by members of the 14-3-3 protein family. However, knowledge about the variation between 14-3-3 proteins in their regulation of TH is still limited. We examined the binding, effects on activation and dephosphorylation kinetics of tyrosine hydroxylase (TH) by abundant midbrain 14-3-3 proteins (β, η, ζ, γ and ε) of different dimer composition. All 14-3-3 homodimers and their respective 14-3-3ε-heterodimers bound with similar high affinity (K d values of 1.4-3.8 nM) to serine19 phosphorylated human TH (TH-pS19). We similarly observed a consistent activation of bovine (3.3- to 4.4-fold) and human TH-pS19 (1.3-1.6 fold) across all the different 14-3-3 dimer species, with homodimeric 14-3-3γ being the strongest activator. Both hetero- and homodimers of 14-3-3 strongly inhibited dephosphorylation of TH-pS19, and we speculate if this is an important homeostatic mechanism of 14-3-3 target-protein regulation in vivo. We conclude that TH is a robust interaction partner of different 14-3-3 dimer types with moderate variability between the 14-3-3 dimers on their regulation of TH.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghorbani
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: Agnete
authors.initials: A
authors.lastname: Fossbakk
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: Ana
authors.initials: A
authors.lastname: Jorge-Finnigan
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Marte I
authors.initials: MI
authors.lastname: Flydal
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.|Haukeland University Hospital, Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway. rune.kleppe@uib.no.|K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway. rune.kleppe@uib.no.
authors.forename: Rune
authors.initials: R
authors.lastname: Kleppe
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D019281:Dimerization; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D016415:Sequence Alignment; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D014446:Tyrosine 3-Monooxygenase
keywords: 14-3-3; Activation; Heterodimer; Isoform; Tyrosine hydroxylase
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