A Carboxyl Terminal Leucine Zipper Is Required for Tyrosine Hydroxylase Tetramer Formation

  title={A Carboxyl Terminal Leucine Zipper Is Required for Tyrosine Hydroxylase Tetramer Formation},
  author={Kent E. Vrana and Shelby J. Walker and P Rucker and X. Liu},
  journal={Journal of Neurochemistry},
Abstract: Tyrosine hydroxylase catalyzes the rate‐limiting reaction in the biosynthesis of the catecholamine neurotransmitters and hormones (dopamine, norepinephrine, and epinephrine). Rat tyrosine hydroxylase exists, in its native form, as a tetramer composed of identical 498 amino acid subunits. There is currently no information describing the molecular interactions by which the four monomeric tyrosine hydroxylase subunits assemble into an active tetramer. Mutational analysis was performed on… 
Identification of amino-terminal sequences contributing to tryptophan hydroxylase tetramer formation
There is information within the amino-terminus that is necessary for tetramer formation of TPH, and an additional intersubunit binding domain in the amino -terminus is similar to that found in the carboxyl- terminus.
Relationship between Enzymatic Activity and Oligomerization State of Tyrosine Hydroxylase.
This work has investigated, by deletion and/or substitution mutagenesis, the involvement of the leucine zipper (LZ) motifs in the oligomer formation of TH and its relation to catalytic activity and demonstrates that deletion of the carboxyl-terminal LZ (Lz-C) abolishes tetramer formation.
Intersubunit binding domains within tyrosine hydroxylase and tryptophan hydroxylase
These studies indicate that, although the proposed salt bridge dimerization interface of TH is conserved in TPH, this hypothetical TPH intersubunit binding domain, K111–E223, is not required for the proper macromolecular assembly of the protein.
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.
Tyrosine hydroxylase and tryptophan hydroxylase do not form heterotetramers
Immunoprecipitation of induced bacterial supernatants with a TPH monoclonal antibody demonstrated that, unlike the human TH isoforms, TH and TPH do not form heterotetramers, and suggests that specificity of oligomerization of the aromatic amino acid hydroxylases may be partially determined by polar amino acids interspersed within the coiled-coil.
A chimeric tyrosine/tryptophan hydroxylase
It is concluded that the regulatory domain of TH functions as a stabilizer of enzyme activity, and the well-characterized instability of TPH may be attributed to the inability of its regulatory domain to stabilize the catalytic domain.
Structure/function relationships in human phenylalanine hydroxylase. Effect of terminal deletions on the oligomerization, activation and cooperativity of substrate binding to the enzyme.
These results are compatible with a model in which incubation of wt-hPAH with L-Phe induces both a conformational change (with cooperativity in the tetrameric enzyme) which relieves the inhibition imposed by the amino-terminal domain to the high-affinity binding of L- Phe, and an additional activation, as observed for the truncated forms lacking the amino -terminal.
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.


Leucine zippers and coiled-coils in the aromatic amino acid hydroxylases
Expression and characterization of catalytic and regulatory domains of rat tyrosine hydroxylase
Results establish that all of the catalytic residues of tyrosine hydroxylase are located in the C‐terminal 330 amino acids, consistent with a model in which the C-terminal two‐thirds constitute a conserved catalytic domain to which has been appended discrete regulatory domains.
Characterization of the catalytic domain of bovine adrenal tyrosine hydroxylase.
Full-length cDNA for rabbit tryptophan hydroxylase: functional domains and evolution of aromatic amino acid hydroxylases.
The pattern of sequence homology supports the hypothesis that the carboxyl-terminal two-thirds of the molecules constitute the enzymatic activity cores, and the amino- terminal thirds of the molecule constitute domains for substrate specificity.
Evidence for leucine zipper motif in lactose repressor protein.
Limited proteolysis of rat brain tyrosine hydroxylase defines an N-terminal region required for regulation of cofactor binding and directing substrate specificity.
  • C. Abate, T. Joh
  • Biology, Chemistry
    Journal of molecular neuroscience : MN
  • 1991
Proteolysis of the N-terminus of tyrosine hydroxylase regulates cofactor binding and directs substrate specificity, and activation of substrate binding was coincident with a broadened substrate specificity.
The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins.
A 30-amino-acid segment of C/EBP, a newly discovered enhancer binding protein, shares notable sequence similarity with a segment of the cellular Myc transforming protein, and may represent a characteristic property of a new category of DNA binding proteins.
Subcellular distribution and aggregation of bovine adrenal tyrosine hydroxylase.
Bovine adrenal tyrosine hydroxylase is a soluble enzyme which is not contained in the catecholamine storage granules, which explains why the enzyme was originally described as particle bound.