Thyroglobulin
Thyroglobulin (Tg) is a 660 kDa, dimeric protein produced by and used entirely within the thyroid gland. Tg bound to T3 and/or T4 is sometimes called a colloid.
Thyroglobulin should not be confused with Thyroxine-binding globulin, a carrier protein responsible for carrying the thyroid hormones in the blood.
Thyroglobulin is produced by the follicular cells of the thyroid.
Function
Tg is used by the thyroid gland to produce the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The active form of triiodothyronine, 3, 5, 3' triiodothyronine, is produced both within the thyroid gland and in the periphery by 5'-deiodinase (which has been referred to as tetraiodothyronine 5' deiodinase). It is presumed that Tg and thyroid are also an important storage of iodine for all body needs, in particular, for many iodine-concentrating organs such as breast, stomach, salivary glands, thymus, choroid plexus and cerebrospinal fluid, etc.[2] (see iodine in biology).
In fact, the Tg molecule, which contains approximately 120 tyrosyl residues, is able to form only very small amounts of thyroid hormone (5-6 molecules of T4 and T3).
Tg is produced by the thyroid epithelial cells, called thyrocytes, which form spherical follicles. Tg is secreted and stored in the follicular lumen.
Via a reaction with the enzyme thyroperoxidase, iodine is covalently bound to tyrosine residues in thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT).
- Thyroxine is produced by combining two moieties of DIT.
- Triiodothyronine is produced by combining one molecule of MIT and one molecule of DIT.
Small globules of the follicular colloid (Tg) are endocytosed (hormone (TSH)-mediated) and proteases in lysosomes digest iodinated thyroglobulin, releasing T3 and T4 within the thyrocyte cytoplasm. The T3 and T4 are then transported across (TSH-mediated) the basolateral thyrocyte membrane, into the bloodstream, by an unknown mechanism while the lysosome is recycled back to the follicular lumen.
Clinical significance
Thyroglobulin levels in the blood are mainly used as a tumor marker[3] for certain kinds of thyroid cancer (particularly papillary or follicular thyroid cancer). Thyroglobulin is not produced by medullary or anaplastic thyroid carcinoma.
Circulating thyroglobulin has a half-life of 65 hours. Following thyroidectomy, it may take many weeks before thyroglobulin levels become undetectable. After thyroglobulin levels become undetectable following thyroidectomy, levels can be serially monitored. A subsequent elevation of the thyroglobulin level is an indication of recurrence of papillary or follicular thyroid carcinoma.
Metabolism of thyroglobulin occurs in the liver and via thyroid gland recycling of the protein.
In the clinical laboratory, thyroglobulin testing can be complicated by the presence of anti-thyroglobulin antibodies (ATA), frequently 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 on thyroglobulin testing. This problem can be somewhat circumvented by testing for the presence of anti-thryroglobulin antibodies. In patients with anti-thyroglobulin antibodies, a better strategy is to not rely on any single lab result but instead to follow serial quantitative measurements. This can help a clinician/clinical pathologist interpret a test and manage patient care, even with the presence of the confounding factor of anti-thyroglobulin antibodies.
Anti-thyroglobulin antibodies are often found in patients with Hashimoto's thyroiditis or Graves' disease. These antibodies are of limited use in the diagnosis of these diseases, since they may also be present in healthy euthyroid individuals. Anti-Tg antibodies are also found in patients with Hashimoto's encephalopathy, a neuroendocrine disorder related to - but not caused by - Hashimoto's thyroiditis.[4]
Interactions
Thyroglobulin has been shown to interact with Binding immunoglobulin protein.[5][6]
References
- ^ Boron WF (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.
- ^ Venturi S, Donati FM, Venturi A, Venturi M (2000). "Environmental iodine deficiency: A challenge to the evolution of terrestrial life?". Thyroid. 10 (8): 727–9. doi:10.1089/10507250050137851. PMID 11014322.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "ACS :: Tumor Markers". American Cancer Society. Retrieved 2009-03-28.
- ^ Ferracci F, Moretto G, Candeago RM, Cimini N, Conte F, Gentile M, Papa N, Carnevale A (2003). "Antithyroid antibodies in the CSF: their role in the pathogenesis of Hashimoto's encephalopathy". Neurology. 60 (4): 712–4. PMID 12601119.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Delom F, Mallet B, Carayon P, Lejeune PJ (2001). "Role of extracellular molecular chaperones in the folding of oxidized proteins. Refolding of colloidal thyroglobulin by protein disulfide isomerase and immunoglobulin heavy chain-binding protein". J. Biol. Chem. 276 (24): 21337–42. doi:10.1074/jbc.M101086200. PMID 11294872.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Delom F, Lejeune PJ, Vinet L, Carayon P, Mallet B (1999). "Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen". Biochem. Biophys. Res. Commun. 255 (2): 438–43. doi:10.1006/bbrc.1999.0229. PMID 10049727.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
Further reading
- Mazzaferri EL, Robbins RJ, Spencer CA; et al. (2003). "A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma". J. Clin. Endocrinol. Metab. 88 (4): 1433–41. doi:10.1210/jc.2002-021702. PMID 12679418.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Henry M, Zanelli E, Piechaczyk M; et al. (1992). "A major human thyroglobulin epitope defined with monoclonal antibodies is mainly recognized by human autoantibodies". Eur. J. Immunol. 22 (2): 315–9. doi:10.1002/eji.1830220205. PMID 1371467.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Targovnik HM, Cochaux P, Corach D, Vassart G (1992). "Identification of a minor Tg mRNA transcript in RNA from normal and goitrous thyroids". Mol. Cell. Endocrinol. 84 (1–2): R23–6. doi:10.1016/0303-7207(92)90087-M. PMID 1639210.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Dunn AD, Crutchfield HE, Dunn JT (1991). "Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L". J. Biol. Chem. 266 (30): 20198–204. PMID 1939080.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Lamas L, Anderson PC, Fox JW, Dunn JT (1989). "Consensus sequences for early iodination and hormonogenesis in human thyroglobulin". J. Biol. Chem. 264 (23): 13541–5. PMID 2760035.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Marriq C, Lejeune PJ, Venot N, Vinet L (1989). "Hormone synthesis in human thyroglobulin: possible cleavage of the polypeptide chain at the tyrosine donor site". FEBS Lett. 242 (2): 414–8. doi:10.1016/0014-5793(89)80513-7. PMID 2914619.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Christophe D, Cabrer B, Bacolla A; et al. (1985). "An unusually long poly(purine)-poly(pyrimidine) sequence is located upstream from the human thyroglobulin gene". Nucleic Acids Res. 13 (14): 5127–44. doi:10.1093/nar/13.14.5127. PMC 321854. PMID 2991855.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Baas F, van Ommen GJ, Bikker H; et al. (1986). "The human thyroglobulin gene is over 300 kb long and contains introns of up to 64 kb". Nucleic Acids Res. 14 (13): 5171–86. doi:10.1093/nar/14.13.5171. PMC 311533. PMID 3016640.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Kubak BM, Potempa LA, Anderson B; et al. (1989). "Evidence that serum amyloid P component binds to mannose-terminated sequences of polysaccharides and glycoproteins". Mol. Immunol. 25 (9): 851–8. doi:10.1016/0161-5890(88)90121-6. PMID 3211159.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Malthiéry Y, Lissitzky S (1987). "Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complementary DNA". Eur. J. Biochem. 165 (3): 491–8. doi:10.1111/j.1432-1033.1987.tb11466.x. PMID 3595599.
- Parma J, Christophe D, Pohl V, Vassart G (1988). "Structural organization of the 5' region of the thyroglobulin gene. Evidence for intron loss and "exonization" during evolution". J. Mol. Biol. 196 (4): 769–79. doi:10.1016/0022-2836(87)90403-7. PMID 3681978.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Bergé-Lefranc JL, Cartouzou G, Mattéi MG; et al. (1985). "Localization of the thyroglobulin gene by in situ hybridization to human chromosomes". Hum. Genet. 69 (1): 28–31. doi:10.1007/BF00295525. PMID 3967888.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Malthiéry Y, Lissitzky S (1985). "Sequence of the 5'-end quarter of the human-thyroglobulin messenger ribonucleic acid and of its deduced amino-acid sequence". Eur. J. Biochem. 147 (1): 53–8. doi:10.1111/j.1432-1033.1985.tb08717.x. PMID 3971976.
- Avvedimento VE, Di Lauro R, Monticelli A; et al. (1985). "Mapping of human thyroglobulin gene on the long arm of chromosome 8 by in situ hybridization". Hum. Genet. 71 (2): 163–6. doi:10.1007/BF00283375. PMID 4043966.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Xiao S, Pollock HG, Taurog A, Rawitch AB (1995). "Characterization of hormonogenic sites in an N-terminal, cyanogen bromide fragment of human thyroglobulin". Arch. Biochem. Biophys. 320 (1): 96–105. doi:10.1006/abbi.1995.1346. PMID 7793989.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Corral J, Martín C, Pérez R; et al. (1993). "Thyroglobulin gene point mutation associated with non-endemic simple goitre". Lancet. 341 (8843): 462–4. doi:10.1016/0140-6736(93)90209-Y. PMID 8094490.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - Gentile F, Salvatore G (1994). "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". Eur. J. Biochem. 218 (2): 603–21. doi:10.1111/j.1432-1033.1993.tb18414.x. PMID 8269951.
- Mallet B, Lejeune PJ, Baudry N; et al. (1996). "N-glycans modulate in vivo and in vitro thyroid hormone synthesis. Study at the N-terminal domain of thyroglobulin". J. Biol. Chem. 270 (50): 29881–8. doi:10.1074/jbc.270.50.29881. PMID 8530385.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - Yang SX, Pollock HG, Rawitch AB (1996). "Glycosylation in human thyroglobulin: location of the N-linked oligosaccharide units and comparison with bovine thyroglobulin". Arch. Biochem. Biophys. 327 (1): 61–70. doi:10.1006/abbi.1996.0093. PMID 8615697.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Molina F, Bouanani M, Pau B, Granier C (1996). "Characterization of the type-1 repeat from thyroglobulin, a cysteine-rich module found in proteins from different families". Eur. J. Biochem. 240 (1): 125–33. doi:10.1111/j.1432-1033.1996.0125h.x. PMID 8797845.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
External links
- Thyroglobulin - Lab Tests Online
- Histology at KUMC endo-endo11
- Overview at colostate.edu
- Histology image: 14302loa – Histology Learning System at Boston University