The importance of thyroglobulin structure for thyroid hormone biosynthesis

Thyroglobulin (Tg) is the most important protein in the thyroid because it provides the matrix for thyroid hormone biosynthesis. Here we review experi mental work, principally from our laboratory, on the relationship between T g structure and hormonogenesis. Early work showed that Tg's most important hormonogenic site was located in a fragment of approximately 26 kDa obtaine d on chemical reduction. With the establishment of the cDNA sequence of Tg, this and other major sites could be localized within Tg's polypeptide chai n. The four major hormonogenic sites, designated A, B, C, and D, are locate d respectively at tyrosyls 5, 2553, 2746, and 1290. In most species, site A accounts for about 40% of Tg's hormone, and site B for about 25%. Site C i s associated with increased T-3, at least in some species. Site D is promin ent in guinea pigs and rabbits, and TSH favors hormonogenesis at it in thes e species. Sequential iodination of low iodine human Tg shows three consens us sequences associated with early iodination and with T-4 formation. Recen t work has identified Tyr(130) in beef Tg as donor of an outer iodothyronin e ring, most Likely to Tyr(5), the most important hormonogenic site. In add ition to its biochemical importance, Tg has clinical interest in familial g oiter and autoimmune thyroid disease. Further elucidation of Tg structure a nd its relation to thyroid hormone synthesis will contribute to thyroid phy siology and to its clinical application. (C) Societe francaise de biochimie et biologie moleculaire / Elsevier, Paris.