Triplets! Unexpected structural similarity among the three enzymes that catalyze initiation and termination of thyroid hormone effects.

Abstract

The three iodothyronine deiodinases catalyze the initiation (D1, D2) and termination (D3) of thyroid hormone effects in vertebrates. A recently conceived 3-dimensional model predicts that these enzymes share a similar structural organization and belong to the thioredoxin (TRX) fold superfamily. Their active center is a selenocysteine-containing pocket defined by the beta1-alpha1-beta2 motifs of the TRX fold and a domain that shares strong similarities with the active site of iduronidase, a member of the clan GH-A fold of glycoside hydrolases. While D1 and D3 are long-lived plasma membrane proteins, D2 is an endoplasmic reticulum resident protein with a half-life of only 20 min. D2 inactivation is mediated by selective UBC-7-mediated conjugation to ubiquitin, a process that is accelerated by T4 catalysis, thus maintaining local T3 homeostasis. In addition, D2 interacts with and is a substrate of the pVHL-interacting deubiquitinating enzymes (VDU1 and VDU2); thus deubiquitination regulates the supply of active thyroid hormone in D2-expressing cells.