title: Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology.
abstract: Thyroglobulin (Tg) is a vertebrate secretory protein synthesized in the thyrocyte endoplasmic reticulum (ER), where it acquires N-linked glycosylation and conformational maturation (including formation of many disulfide bonds), leading to homodimerization. Its primary functions include iodide storage and thyroid hormonogenesis. Tg consists largely of repeating domains, and many tyrosyl residues in these domains become iodinated to form monoiodo- and diiodotyrosine, whereas only a small portion of Tg structure is dedicated to hormone formation. Interestingly, evolutionary ancestors, dependent upon thyroid hormone for development, synthesize thyroid hormones without the complete Tg protein architecture. Nevertheless, in all vertebrates, Tg follows a strict pattern of region I, II-III, and the cholinesterase-like (ChEL) domain. In vertebrates, Tg first undergoes intracellular transport through the secretory pathway, which requires the assistance of thyrocyte ER chaperones and oxidoreductases, as well as coordination of distinct regions of Tg, to achieve a native conformation. Curiously, regions II-III and ChEL behave as fully independent folding units that could function as successful secretory proteins by themselves. However, the large Tg region I (bearing the primary T4-forming site) is incompetent by itself for intracellular transport, requiring the downstream regions II-III and ChEL to complete its folding. A combination of nonsense mutations, frameshift mutations, splice site mutations, and missense mutations in Tg occurs spontaneously to cause congenital hypothyroidism and thyroidal ER stress. These Tg mutants are unable to achieve a native conformation within the ER, interfering with the efficiency of Tg maturation and export to the thyroid follicle lumen for iodide storage and hormonogenesis.
authors.affiliation: Laboratorio di Patologia Generale (B.D.J.), Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, 73100 Lecce, Italy; and Division of Metabolism, Endocrinology, and Diabetes (P.A.), University of Michigan Medical School, Ann Arbor, Michigan 48105.
authors.forename: Bruno
authors.initials: B
authors.lastname: Di Jeso
authors.affiliation: Laboratorio di Patologia Generale (B.D.J.), Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, 73100 Lecce, Italy; and Division of Metabolism, Endocrinology, and Diabetes (P.A.), University of Michigan Medical School, Ann Arbor, Michigan 48105.
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D000818:Animals; D003409:Congenital Hypothyroidism / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress; D020022:Genetic Predisposition to Disease; D054879:Halogenation; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D013954:Thyroglobulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013961:Thyroid Gland / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology
chemical_list: D013954:Thyroglobulin