Thyroglobulin structure, function, and biosynthesis.

Abstract

Thyroglobulin (TG), a homodimeric glycoprotein of 660 kDa (TG 19S), functions as the highly specialized matrix for thyroid hormone biosynthesis and for the storage of the inactive form of thyroid hormones and iodine (1). TG is translocated into the endoplasmic reticulum (ER). During translation/translocation, newly synthesized TG immediately starts to fold and acquires its final glycoprotein structure as it passes through the Golgi complex. Correct folding is determined in large part by the sequence of the protein, but it is also assisted by interaction with enzymes and chaperones of the ER. TG is finally secreted and stored in the follicular lumen as colloid. The iodine content of TG under normal conditions varies widely depending on iodine intake and species. For normal human TG, values from 0.1% to 1.1% (from 5 to 55 atoms of iodine per mole of TG) have been reported (2). The iodine is covalently bound to amino acids within TG in the form of T3, T4, and their iodotyrosine inactive precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT) (1). TG contains even low amounts of 3,3´,5´-iodothyronine (rT3), 3,3´-diiodothyronine (T2), and monoiodohistidine (3¨C5). The thyroid cells produce free thyroid hormones by proteolytic cleavage of the TG (6), which are delivered to the blood circulation for action at their peripheral target tissues. Biosynthesis of thyroid hormones requires the integrity of a complex protein system, several sequential steps, and is critically dependent upon the native three-dimensional structure of TG. The general organization of the TG gene, its mRNA, and protein domains has been studied extensively (1). However, little is known about the structure function relationship of the TG because of our lack of knowledge about the three-dimensional structure of this protein. Unfortunately, there are no X-ray crystallographic data of any TG regions due to the numerous posttranslational modifications. The TG is also a possible regulator of thyroid follicle function (7¨C9) or could be involved in some unknown mechanisms that remain to be explored.