Examination of interaction between regulatory domain of tyrosine hydroxylase and 14-3-3 protein

A. Brzóstowicz^1,2, M. Makovická^1,2

1. CEITEC-MU, Kamenice 5, 625 00, Brno, Czech Republic, jozef.hritz@gmail.com

2. National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic

al.brzostowicz@gmail.com

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis belonging to aromatic amino acid hydroxylases (AAAHs) family [1]. Enzymatic reaction results in hydroxylation of L-tyrosine into L-DOPA, a precursor of crucial neurotransmitters in human body: dopamine, norepinephrine and epinephrine which deficiencies lead to neurological disorders like Alzheimer disease, dystonia and Segawa syndrome [2].

TH has a multi-domain structure with unstructured amino-terminal regulatory domain (RD) followed by catalytic domain and coiled-coil domain responsible for oligomerization at the carboxyl terminus. Enzyme activation is mostly held by phosphorylation of both Ser-19 and Ser-40 residues [3]. These two modifications enable to form a complex with 14-3-3 protein with high affinity and provides TH stabilization and proteolytic protection of the regulatory domain N-terminus [3]. Although TH was first reported enzyme interacting with 14-3-3 protein, the exact mode of its regulation still needs further investigation to provide the molecular targets in drug development [4].

[1]       Kaufman, S. (1985). Regulatory properties of phenylalanine, tyrosine and tryptophan hydroxylases. Biochemical Society Transactions, 13(2), 433–436.

[2]       Willemsen, M. A., Verbeek, M. M., Kamsteeg, E.-J., de Rijk-van Andel, J. F., Aeby, A., Blau, N., Wevers, R. A. (2010). Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain, 133(6), 1810–1822.

[3]       Daubner, S. C., Le, T., & Wang, S. (2011). Tyrosine hydroxylase and regulation of dopamine synthesis. Archives of Biochemistry and Biophysics, 508(1), 1–12.

[4]       Ichimura, T., Isobe, T., Okuyama, T., Yamauchi, T., & Fujisawa, H. (1987). Brain 14-3-3 protein is an activator protein that activates tryptophan 5-monooxygenase and tyrosine 3-monooxygenase in the presence of Ca2+,calmodulin-dependent protein kinase II. FEBS Letters, 219(1), 79–82.