Tyrosine and tryptophan hydroxylase are the rate-limiting enzymes in the biosynthesis of the catecholamines (dopamine, norepinephrine and epinephrine) and serotonin, respectively. Along with phenyl alanine hydroxylase, they comprise members of the aromatic amino acid hydroxylase superfamily. The enzymes share a number of physical and catalytic properties. In particular, each of the proteins is known to assemble into homotetramers. We propose that this subunit assembly may be accomplished using a recently described protein folding motif termed the leucine zipper. The leucine zipper was originally described as an integral factor in the dimerization of eukaryotic DNA-binding proteins. This folding motif is characterized by the heptadic repeat of leucine residues in an alpha helix. This repetition results in the presence of an array of leucine residues on one face of the helix. Such leucine residues, on separate helices, are then thought to interdigitate to form the leucine zipper. A variant of this structure has been proposed in which additional hydrophobic residues are positioned three amino acids from the leucines (producing a 4-3 repeat of hydrophobic amino acids). Two such helices could then coil about one another (interacting at a hydrophobic interface) producing a coiled-coil structure characteristic of fibrous proteins. Analysis of the primary amino acid sequences of the aromatic amino acid hydroxylases identifies three highly conserved regions possessing leucine zipper or coiled-coil characteristics. These domains may provide the physical basis for the protein-protein interactions required to effect the assembly of these important enzymes into their native, multisubunit conformations.