Thyroglobulin is the major protein of the thyroid. It provides a matrix for the synthesis of the thyroid hormones and a vehicle for their subsequent storage. Our long range objectives are to define its role in the synthesis and release of thyroid hormones, and to investigate the possibility that variuations in its structure may lead to goiter in humans. In work to date we have found that reduced throglobulin from a number of species contains discrete thyroxine-rich peptides of small size, and the distribution of iodine among them is influenced by the amount of iodine available and by TSH. We have also described a number of lysosomal proteases which digest thyroglobulin and thereby effect the release of hormone. In addition, we have found variations in the structure of thyroglobulin from normal thyroids, and even more variation in that from goiters and thyroid cancer. We plan further experiments as follows: (1) To define the origins of the thyroxine-rich peptides of reduced thyroglobulin, we will study their amino acid incorporation in vitro, the effects of time, iodine deficiency, and TSH in vivo, the variation among normal and goitrous human glands and among different vertebrate species, and the site from which the outer ring of thyroxine is donated. (2) We plan to sequence key parts of the thyrozine-rich peptides to identify the chemical features important to hormone synthesis. (3) The physiological steps in Tg breakdown and hormone release will be evaluated by further purification and characterization of thiol endopeptidases and of exopeptidases, by characterization of the thyroxine-rich fragments produced by these proteases, by investigation of TSH's role in the rate of proteolysis, and by in vitro models for the physiological hydrolysis of thyglobulin.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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University of Virginia
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Dunn, J T; Dunn, A D (1999) The importance of thyroglobulin structure for thyroid hormone biosynthesis. Biochimie 81:505-9
Colzani, R M; Alex, S; Dunn, A D et al. (1999) The oral administration of human thyroglobulin does not affect the incidence of lymphocytic thyroiditis in the biobreeding Worcester rat. Thyroid 9:831-5
Dunn, A D; Corsi, C M; Myers, H E et al. (1998) Tyrosine 130 is an important outer ring donor for thyroxine formation in thyroglobulin. J Biol Chem 273:25223-9
Dunn, A D; Myers, H E; Dunn, J T (1996) The combined action of two thyroidal proteases releases T4 from the dominant hormone-forming site of thyroglobulin. Endocrinology 137:3279-85
Mason, M E; Struyk, B P; Dunn, J T (1996) mRNA encoding human thyroglobulin's C-terminus is heterogeneous. Thyroid 6:633-7
Mason, M E; Dunn, A D; Wortsman, J et al. (1995) Thyroids from siblings with Pendred's syndrome contain thyroglobulin messenger ribonucleic acid variants. J Clin Endocrinol Metab 80:497-503
Dunn, A D; Crutchfield, H E; Dunn, J T (1991) Proteolytic processing of thyroglobulin by extracts of thyroid lysosomes. Endocrinology 128:3073-80
Dunn, A D; Crutchfield, H E; Dunn, J T (1991) Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L. J Biol Chem 266:20198-204
Lamas, L; Anderson, P C; Fox, J W et al. (1989) Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J Biol Chem 264:13541-5
Roe, M T; Anderson, P C; Dunn, A D et al. (1989) The hormonogenic sites of turtle thyroglobulin and their homology with those of mammals. Endocrinology 124:1327-32

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