Biology:Thyroglobulin

Short description: Protein produced and used by the thyroid

Generic protein structure example

Thyroglobulin (Tg) is a 660 kDa, dimeric glycoprotein produced by the follicular cells of the thyroid and used entirely within the thyroid gland. Tg is secreted and accumulated at hundreds of grams per litre in the extracellular compartment of the thyroid follicles, accounting for approximately half of the protein content of the thyroid gland. Human TG (hTG) is a homodimer of subunits each containing 2768 amino acids as synthesized (a short signal peptide of 19 amino acids may be removed from the N-terminus in the mature protein).

Thyroglobulin is in all vertebrates the main precursor to thyroid hormones, which are produced when thyroglobulin's tyrosine residues are combined with iodine and the protein is subsequently cleaved. Each thyroglobulin molecule contains approximately 16 tyrosine residues, but only a small number 10 of these are subject to iodination by thyroperoxidase in the follicular colloid. Therefore, each Tg molecule forms approximately 10 thyroid hormone molecules.

Function

Thyroid hormone synthesis, this image traces thyroglobulin from production within the rough endoplasmic reticulum until proteolytic release of the thyroid hormones.

Thyroglobulin (Tg) acts as a substrate for the synthesis of the thyroid hormones thyroxine (T4) and triiodothyronine (T3), as well as the storage of the inactive forms of thyroid hormone and iodine within the follicular lumen of a thyroid follicle.

Newly synthesized thyroid hormones (T3 and T4) are attached to thyroglobulin and comprise the colloid within the follicle. When stimulated by thyroid stimulating hormone (TSH), the colloid is endocytosed from the follicular lumen into the surrounding thyroid follicular epithelial cells. The colloid is subsequently cleaved by proteases to release thyroglobulin from its T3 and T4 attachments.

The active forms of thyroid hormone: T3 and T4, are then released into circulation where they are either unbound or attached to plasma proteins, and thyroglobulin is recycled back into the follicular lumen where it can continue to serve as a substrate for thyroid hormone synthesis.

Clinical significance

Half-life and clinical elevation

Metabolism of thyroglobulin occurs in the liver via thyroid gland recycling of the protein. Circulating thyroglobulin has a half-life of 65 hours. Following thyroidectomy, it may take many weeks before thyroglobulin levels become undetectable. Thyroglobulin levels may be tested regularly for a few weeks or months following the removal of the thyroid. After thyroglobulin levels become undetectable (following thyroidectomy), levels can be serially monitored in follow-up of patients with papillary or follicular thyroid carcinoma.

A subsequent elevation of the thyroglobulin level is an indication of recurrence of papillary or follicular thyroid carcinoma. In other words, a rise in thyroglobulin levels in the blood may be a sign that thyroid cancer cells are growing and/or the cancer is spreading. Hence, thyroglobulin levels in the blood are mainly used as a tumor marker for certain kinds of thyroid cancer (particularly papillary or follicular thyroid cancer). Thyroglobulin is not produced by medullary or anaplastic thyroid carcinoma.

Thyroglobulin levels are tested via a simple blood test. Tests are often ordered after thyroid cancer treatment.

Thyroglobulin antibodies

In the clinical laboratory, thyroglobulin testing can be complicated by the presence of anti-thyroglobulin antibodies (ATAs, alternatively referred to as TgAb). Anti-thyroglobulin antibodies are present in 1 in 10 normal individuals, and a greater percentage of patients with thyroid carcinoma. The presence of these antibodies can result in falsely low (or rarely falsely high) levels of reported thyroglobulin, a problem that can be somewhat circumvented by concomitant testing for the presence of ATAs. The ideal strategy for a clinician's interpretation and management of patient care in the event of confounding detection of ATAs is testing to follow serial quantitative measurements (rather than a single laboratory measurement).

ATAs are often found in patients with Hashimoto's thyroiditis or Graves' disease. Their presence is of limited use in the diagnosis of these diseases, since they may also be present in healthy euthyroid individuals. ATAs are also found in patients with Hashimoto's encephalopathy, a neuroendocrine disorder related to—but not caused by—Hashimoto's thyroiditis.

Interactions

Thyroglobulin has been shown to interact with Binding immunoglobulin protein.

Further reading

• "The structure of human thyroglobulin". Nature 578 (7796): 627–630. February 2020. doi:10.1038/s41586-020-1995-4. PMID 32025030. Bibcode: 2020Natur.578..627C. 
• "A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma". The Journal of Clinical Endocrinology and Metabolism 88 (4): 1433–1441. April 2003. doi:10.1210/jc.2002-021702. PMID 12679418. 
• "A major human thyroglobulin epitope defined with monoclonal antibodies is mainly recognized by human autoantibodies". European Journal of Immunology 22 (2): 315–319. February 1992. doi:10.1002/eji.1830220205. PMID 1371467. 
• "Identification of a minor Tg mRNA transcript in RNA from normal and goitrous thyroids". Molecular and Cellular Endocrinology 84 (1–2): R23–R26. March 1992. doi:10.1016/0303-7207(92)90087-M. PMID 1639210. 
• "Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L". The Journal of Biological Chemistry 266 (30): 20198–20204. October 1991. doi:10.1016/S0021-9258(18)54909-7. PMID 1939080. 
• "Consensus sequences for early iodination and hormonogenesis in human thyroglobulin". The Journal of Biological Chemistry 264 (23): 13541–13545. August 1989. doi:10.1016/S0021-9258(18)80031-X. PMID 2760035. 
• "Hormone synthesis in human thyroglobulin: possible cleavage of the polypeptide chain at the tyrosine donor site". FEBS Letters 242 (2): 414–418. January 1989. doi:10.1016/0014-5793(89)80513-7. PMID 2914619. 
• "An unusually long poly(purine)-poly(pyrimidine) sequence is located upstream from the human thyroglobulin gene". Nucleic Acids Research 13 (14): 5127–5144. July 1985. doi:10.1093/nar/13.14.5127. PMID 2991855. 
• "The human thyroglobulin gene is over 300 kb long and contains introns of up to 64 kb". Nucleic Acids Research 14 (13): 5171–5186. July 1986. doi:10.1093/nar/14.13.5171. PMID 3016640. 
• "Evidence that serum amyloid P component binds to mannose-terminated sequences of polysaccharides and glycoproteins". Molecular Immunology 25 (9): 851–858. September 1988. doi:10.1016/0161-5890(88)90121-6. PMID 3211159. 
• "Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complementary DNA". European Journal of Biochemistry 165 (3): 491–498. June 1987. doi:10.1111/j.1432-1033.1987.tb11466.x. PMID 3595599. 
• "Structural organization of the 5' region of the thyroglobulin gene. Evidence for intron loss and "exonization" during evolution". Journal of Molecular Biology 196 (4): 769–779. August 1987. doi:10.1016/0022-2836(87)90403-7. PMID 3681978. 
• "Localization of the thyroglobulin gene by in situ hybridization to human chromosomes". Human Genetics 69 (1): 28–31. 1985. doi:10.1007/BF00295525. PMID 3967888. 
• "Sequence of the 5'-end quarter of the human-thyroglobulin messenger ribonucleic acid and of its deduced amino-acid sequence". European Journal of Biochemistry 147 (1): 53–58. February 1985. doi:10.1111/j.1432-1033.1985.tb08717.x. PMID 3971976. 
• "Mapping of human thyroglobulin gene on the long arm of chromosome 8 by in situ hybridization". Human Genetics 71 (2): 163–166. 1985. doi:10.1007/BF00283375. PMID 4043966. 
• "Characterization of hormonogenic sites in an N-terminal, cyanogen bromide fragment of human thyroglobulin". Archives of Biochemistry and Biophysics 320 (1): 96–105. June 1995. doi:10.1006/abbi.1995.1346. PMID 7793989. 
• "Thyroglobulin gene point mutation associated with non-endemic simple goitre". Lancet 341 (8843): 462–464. February 1993. doi:10.1016/0140-6736(93)90209-Y. PMID 8094490. 
• "Preferential sites of proteolytic cleavage of bovine, human and rat thyroglobulin. The use of limited proteolysis to detect solvent-exposed regions of the primary structure". European Journal of Biochemistry 218 (2): 603–621. December 1993. doi:10.1111/j.1432-1033.1993.tb18414.x. PMID 8269951. 
• "N-glycans modulate in vivo and in vitro thyroid hormone synthesis. Study at the N-terminal domain of thyroglobulin". The Journal of Biological Chemistry 270 (50): 29881–29888. December 1995. doi:10.1074/jbc.270.50.29881. PMID 8530385. 
• "Glycosylation in human thyroglobulin: location of the N-linked oligosaccharide units and comparison with bovine thyroglobulin". Archives of Biochemistry and Biophysics 327 (1): 61–70. March 1996. doi:10.1006/abbi.1996.0093. PMID 8615697. 
• "Characterization of the type-1 repeat from thyroglobulin, a cysteine-rich module found in proteins from different families". European Journal of Biochemistry 240 (1): 125–133. August 1996. doi:10.1111/j.1432-1033.1996.0125h.x. PMID 8797845. 
• "Thyroglobulin in lymph node fine-needle aspiration washout: a systematic review and meta-analysis of diagnostic accuracy". The Journal of Clinical Endocrinology and Metabolism 99 (6): 1970–1982. June 2014. doi:10.1210/jc.2014-1098. PMID 24617715. 

External links

• First look at the structure of human TG
• Thyroglobulin – Lab Tests Online
• Histology at KUMC endo-endo11
• Overview at colostate.edu
• Histology image: 14302loa – Histology Learning System at Boston University