Detalle de: The Structure of Human Tyrosine Hydroxylase Reveals the Mechanism for Feedback Inhibition by Dopamine

Tyrosine hydroxylase (TH) is a highly regulated enzyme that catalyses the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines. Mutations and dysfunction in this enzyme lead to DA deficiency and parkinsonisms of different severity. An understanding of TH deficiency at the level of structure and stability has been lacking to date, as only structures of truncated TH forms have been available. Here, we used cryoEM to determine the first high-resolution structure of full-length human tetrameric TH in the absence (3.4 Å) and presence (3.8 Å) of the end-product and feedback inhibitor DA bound to the active site. We show that upon DA binding, an α-helix (residues 39-59) included within the flexible N-terminal tail of the regulatory domain, is internalized in the active site. The observed structural changes reveal the molecular basis of the inhibitory and stabilizing DA effect, reversible by TH S40-phosphorylation, which are crucial regulatory mechanisms for catecholamine and TH homeostasis.