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=== Expression of the TG gene===
=== Expression of the TG gene===
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Thyroid follicular cells synthesize human <scene name='86/868183/Full_tg/2'>TG</scene> via the TG gene on chromosome 8.
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Thyroid follicular cells synthesize human <scene name='86/868183/Tg/3'>TG</scene> via the TG gene on chromosome 8.
=== Post-translational modifications ===
=== Post-translational modifications ===
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TG also undergoes N-glycosylations in the ER at 17 <scene name='86/868183/Carbohydrated/1'>glycosylation sites</scene>, so that 10% of its molecular weight is carbohydrate. These modifications enhance its stability and solubility. Indeed, the two monomers are linked not by covalent interactions but via numerous interactions allowed by these N-glycosylations.
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TG also undergoes N-glycosylations in the ER at <scene name='86/868183/Glycosylation_sites/1'>17 glycosylation sites</scene>, so that 10% of its molecular weight is carbohydrate. These modifications enhance its stability and solubility. Indeed, the two monomers are linked not by covalent interactions but via numerous interactions allowed by these N-glycosylations.
=== Folding ===
=== Folding ===
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In the colloid, about 30 tyrosines out of the 66 tyrosines, each consisting of a phenol group, are iodized. The quantity of iodinated tyrosine depends however on the iodide concentration of the colloid. Indeed, one or two iodide ions can be covalently bound to the colloid and thus give a di (DIT) or mono-iodinated (MIT) phenol group. The iodination of the phenol groups is carried out by two membrane enzymes of the follicular cells: the double oxidase (DUOX) synthesizes the hydrogen peroxide H2O2 necessary for thyroid peroxidase (TPO).
In the colloid, about 30 tyrosines out of the 66 tyrosines, each consisting of a phenol group, are iodized. The quantity of iodinated tyrosine depends however on the iodide concentration of the colloid. Indeed, one or two iodide ions can be covalently bound to the colloid and thus give a di (DIT) or mono-iodinated (MIT) phenol group. The iodination of the phenol groups is carried out by two membrane enzymes of the follicular cells: the double oxidase (DUOX) synthesizes the hydrogen peroxide H2O2 necessary for thyroid peroxidase (TPO).
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Due to the spatial conformation of <scene name='86/868183/Full_tg/2'>TG</scene>, there is a transfer of di or mono iodinated aromatic ring from a donor tyrosine to a close acceptor diiodotyrosine for the 14 tyrosines of the hormonogenic sites. Acceptor iodinated tyrosines are DITs because they are deprotonated due to their 6.5 acid pka facilitating the acceptance reaction leading to the formation of quinol-ether bonds, whereas donor iodinated tyrosines are MITs with a pKa of 8.5<ref>DOI 10.1530/eje.0.1380227</ref>.
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Due to the spatial conformation of <scene name='86/868183/Tg/3'>TG</scene>, there is a transfer of di- or mono-iodinated aromatic ring from a donor tyrosine to a close acceptor diiodotyrosine for the 14 tyrosines of the hormonogenic sites. Acceptor iodinated tyrosines are DITs because they are deprotonated due to their 6.5 acid pka facilitating the acceptance reaction leading to the formation of quinol-ether bonds, whereas donor iodinated tyrosines are MITs with a pKa of 8.5<ref>DOI 10.1530/eje.0.1380227</ref>.
At the end of the coupling, the donor tyrosines are left with a dehydroalanine.
At the end of the coupling, the donor tyrosines are left with a dehydroalanine.
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Once iodization and coupling have been performed, endocytosis of the colloid to the lysosome occurs. The <scene name='86/868183/Full_tg/2'>TG</scene> is proteolyzed by cathepsin proteases<ref>DOI 1939080</ref> and 7 TH are thus released from 14 mono- or di iodinated tyrosines.
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Once iodization and coupling have been performed, endocytosis of the colloid to the lysosome occurs. The <scene name='86/868183/Tg/3'>TG</scene> is proteolyzed by cathepsin proteases<ref>DOI 1939080</ref> and 7 TH are thus released from 14 mono- or di-iodinated tyrosines.
The hormone synthesis function of TG is thus particularly linked to its structure. Moreover, research shows that denaturation or a simple modification of its conformation prevents the formation of TH <ref>PMID:4710237</ref><ref>DOI 456595</ref>.
The hormone synthesis function of TG is thus particularly linked to its structure. Moreover, research shows that denaturation or a simple modification of its conformation prevents the formation of TH <ref>PMID:4710237</ref><ref>DOI 456595</ref>.
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=== Iodine tank ===
=== Iodine tank ===
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The complex and particularly stable structure of <scene name='86/868183/Full_tg/2'>TG</scene> gives it iodide reservoir properties. Indeed, all iodinated but non-hormonoid tyrosines are useful for iodine storage in the thyroid gland.
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The complex and particularly stable structure of <scene name='86/868183/Tg/3'>TG</scene> gives it iodide reservoir properties. Indeed, all iodinated but non-hormonoid tyrosines are useful for iodine storage in the thyroid gland.
== Interest in the medical field<ref>DOI 17614775</ref><ref>DOI 10.1677/ERC-10-0292</ref><ref>DOI 5773064</ref><ref>DOI 3681445</ref><ref>DOI 12089177</ref><ref>DOI 21134539</ref><ref>DOI 6814409</ref><ref>DOI 29984794</ref><ref>DOI 26595189</ref> ==
== Interest in the medical field<ref>DOI 17614775</ref><ref>DOI 10.1677/ERC-10-0292</ref><ref>DOI 5773064</ref><ref>DOI 3681445</ref><ref>DOI 12089177</ref><ref>DOI 21134539</ref><ref>DOI 6814409</ref><ref>DOI 29984794</ref><ref>DOI 26595189</ref> ==
=== Modification of the TG quantity related to the desease ===
=== Modification of the TG quantity related to the desease ===
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A healthy subject has between 5 and 25 µg of TG per liter of blood. In case of thyroid dysfunction, this level may increase or decrease. For example, it decreases in the case of congenital athyreosis (insufficiency of the thyroid gland) or prior to a miscarriage due to the presence of anti-TG antibodies, but increases in the case of cancer, thyroiditis, inflammation of the thyroid or autoimmune thyroid diseases AITD <ref>DOI 24147207</ref>(Grave's disease, Hashimoto's thyroiditis).<ref>DOI 11788684</ref>
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A healthy subject has between '''5 and 25 µg of TG per liter''' of blood. In case of thyroid dysfunction, this level may increase or decrease. For example, it decreases in the case of congenital athyreosis (insufficiency of the thyroid gland) or prior to a miscarriage due to the presence of anti-TG antibodies, but increases in the case of cancer, thyroiditis, inflammation of the thyroid or autoimmune thyroid diseases '''AITD''' <ref>DOI 24147207</ref>(Grave's disease, Hashimoto's thyroiditis).<ref>DOI 11788684</ref>
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In addition, a decrease in the size or capacity of the thyroid causes a decrease in the synthesis of TH by the <scene name='86/868183/Full_tg/2'>TG</scene>, and thus a drop in the blood level of T4 and T3, which in turn causes heart disease, brain disease and abnormalities in the development of the fetus. <ref>DOI 29246752</ref><ref>DOI 28593684</ref><ref>DOI 12721190</ref>
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In addition, a decrease in the size or capacity of the thyroid causes a decrease in the synthesis of TH by the <scene name='86/868183/Tg/3'>TG</scene>, and thus a drop in the blood level of T4 and T3, which in turn causes heart disease, brain disease and abnormalities in the development of the fetus. <ref>DOI 29246752</ref><ref>DOI 28593684</ref><ref>DOI 12721190</ref>
The variation of the quantity of TG can thus be as much a cause as a consequence of disease.<ref>DOI 17201802</ref>
The variation of the quantity of TG can thus be as much a cause as a consequence of disease.<ref>DOI 17201802</ref>
=== Use of TG to treat deseases ===
=== Use of TG to treat deseases ===
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A classic TSH-stimulated <scene name='86/868183/Full_tg/2'>TG</scene> measurement or ultrasensitive <scene name='86/868183/Full_tg/2'>TG</scene> measurement allows to control its rate in a more or less sensitive way and therefore to detect a disease like those mentioned above, to ensure the effectiveness of a treatment and the absence of recurrence and to avoid
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A classic '''TSH-stimulated''' <scene name='86/868183/Tg/3'>TG</scene> measurement or ultrasensitive <scene name='86/868183/Tg/3'>TG</scene> measurement allows to control its rate in a more or less sensitive way and therefore to detect a disease like those mentioned above, to ensure the effectiveness of a treatment and the absence of recurrence and to avoid
miscarriages.
miscarriages.
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Since serum <scene name='86/868183/Full_tg/2'>TG</scene> levels are correlated with the volume of thyroid tissue, we can also estimate the mass of thyroid tissue to detect hyperthyroidism, a disease related to an enlarged thyroid or, conversely, hypothyroidism.
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Since serum <scene name='86/868183/Tg/3'>TG</scene> levels are correlated with the volume of thyroid tissue, we can also estimate the mass of thyroid tissue to detect '''hyperthyroidism''', a disease related to an enlarged thyroid or, conversely, '''hypothyroidism'''.
For example, thyroidectomy and a iodine-131 therapy can be performed to cure thyroid cancer with an 80% chance. Following removal and iodine-131 therapy, thyroglobulin is this time produced by malignant thyrocytes. As a result, its blood level is indistinguishable from that of a healthy person. <ref>PMID: 762873</ref><ref>DOI 21649472</ref>
For example, thyroidectomy and a iodine-131 therapy can be performed to cure thyroid cancer with an 80% chance. Following removal and iodine-131 therapy, thyroglobulin is this time produced by malignant thyrocytes. As a result, its blood level is indistinguishable from that of a healthy person. <ref>PMID: 762873</ref><ref>DOI 21649472</ref>
But in case of recurrence and persistence of cancer, its level can increase again. Thyroglobulin therefore always serves as a tumor marker allowing us to estimate the risk of recurrence (>2ng/ml) or persistence (>1ng/ml) or remission.
But in case of recurrence and persistence of cancer, its level can increase again. Thyroglobulin therefore always serves as a tumor marker allowing us to estimate the risk of recurrence (>2ng/ml) or persistence (>1ng/ml) or remission.
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Revision as of 22:10, 11 January 2022

This Sandbox is Reserved from 26/11/2020, through 26/11/2021 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1643 through Sandbox Reserved 1664.
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Human thyroglobulin (TG)

Human thyroglobulin

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References

  1. ↑ Coscia F, Taler-Vercic A, Chang VT, Sinn L, O'Reilly FJ, Izore T, Renko M, Berger I, Rappsilber J, Turk D, Lowe J. The structure of human thyroglobulin. Nature. 2020 Feb 5. pii: 10.1038/s41586-020-1995-4. doi:, 10.1038/s41586-020-1995-4. PMID:32025030 doi:http://dx.doi.org/10.1038/s41586-020-1995-4
  2. ↑ Parma J, Christophe D, Pohl V, Vassart G. Structural organization of the 5' region of the thyroglobulin gene. Evidence for intron loss and "exonization" during evolution. J Mol Biol. 1987 Aug 20;196(4):769-79. PMID:3681978
  3. ↑ Mendive FM, Rivolta CM, Moya CM, Vassart G, Targovnik HM. Genomic organization of the human thyroglobulin gene: the complete intron-exon structure. Eur J Endocrinol. 2001 Oct;145(4):485-96. doi: 10.1530/eje.0.1450485. PMID:11581009 doi:http://dx.doi.org/10.1530/eje.0.1450485
  4. ↑ Malthiery Y, Lissitzky S. Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complementary DNA. Eur J Biochem. 1987 Jun 15;165(3):491-8. PMID:3595599
  5. ↑ van de Graaf SA, Ris-Stalpers C, Pauws E, Mendive FM, Targovnik HM, de Vijlder JJ. Up to date with human thyroglobulin. J Endocrinol. 2001 Aug;170(2):307-21. doi: 10.1677/joe.0.1700307. PMID:11479128 doi:http://dx.doi.org/10.1677/joe.0.1700307
  6. ↑ Brocas H, Christophe D, Pohl V, Vassart G. Cloning of human thyroglobulin complementary DNA. FEBS Lett. 1982 Jan 25;137(2):189-92. doi: 10.1016/0014-5793(82)80346-3. PMID:6895876 doi:http://dx.doi.org/10.1016/0014-5793(82)80346-3
  7. ↑ Baas F, van Ommen GJ, Bikker H, Arnberg AC, de Vijlder JJ. The human thyroglobulin gene is over 300 kb long and contains introns of up to 64 kb. Nucleic Acids Res. 1986 Jul 11;14(13):5171-86. doi: 10.1093/nar/14.13.5171. PMID:3016640 doi:http://dx.doi.org/10.1093/nar/14.13.5171
  8. ↑ Di Jeso B, Ulianich L, Pacifico F, Leonardi A, Vito P, Consiglio E, Formisano S, Arvan P. Folding of thyroglobulin in the calnexin/calreticulin pathway and its alteration by loss of Ca2+ from the endoplasmic reticulum. Biochem J. 2003 Mar 1;370(Pt 2):449-58. doi: 10.1042/BJ20021257. PMID:12401114 doi:http://dx.doi.org/10.1042/BJ20021257
  9. ↑ de Vijlder JJ, den Hartog MT. Anionic iodotyrosine residues are required for iodothyronine synthesis. Eur J Endocrinol. 1998 Feb;138(2):227-31. doi: 10.1530/eje.0.1380227. PMID:9506870 doi:http://dx.doi.org/10.1530/eje.0.1380227
  10. ↑ Dunn AD, Crutchfield HE, Dunn JT. Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L. J Biol Chem. 1991 Oct 25;266(30):20198-204. PMID:1939080
  11. ↑ Rolland M, Montfort MF, Lissitzky S. Efficiency of thyroglobulin as a thyroid hormone-forming protein. Biochim Biophys Acta. 1973 Apr 20;303(2):338-47. doi:, 10.1016/0005-2795(73)90365-6. PMID:4710237 doi:http://dx.doi.org/10.1016/0005-2795(73)90365-6
  12. ↑ Maurizis JC, Marriq C, Michelot J, Rolland M, Lissitzky S. Thyroid peroxidase-induced thyroid hormone synthesis in relation to thyroglobulin structure. FEBS Lett. 1979 Jun 1;102(1):82-6. doi: 10.1016/0014-5793(79)80933-3. PMID:456595 doi:http://dx.doi.org/10.1016/0014-5793(79)80933-3
  13. ↑ Fassler CA, Dunn JT, Anderson PC, Fox JW, Dunn AD, Hite LA, Moore RC, Kim PS. Thyrotropin alters the utilization of thyroglobulin's hormonogenic sites. J Biol Chem. 1988 Nov 25;263(33):17366-71. PMID:3182849
  14. ↑ Di Jeso B, Liguoro D, Ferranti P, Marinaccio M, Acquaviva R, Formisano S, Consiglio E. Modulation of the carbohydrate moiety of thyroglobulin by thyrotropin and calcium in Fisher rat thyroid line-5 cells. J Biol Chem. 1992 Jan 25;267(3):1938-44. PMID:1370485
  15. ↑ Leboeuf R, Emerick LE, Martorella AJ, Tuttle RM. Impact of pregnancy on serum thyroglobulin and detection of recurrent disease shortly after delivery in thyroid cancer survivors. Thyroid. 2007 Jun;17(6):543-7. doi: 10.1089/thy.2007.0020. PMID:17614775 doi:http://dx.doi.org/10.1089/thy.2007.0020
  16. ↑ Nascimento C, Borget I, Al Ghuzlan A, Deandreis D, Chami L, Travagli JP, Hartl D, Lumbroso J, Chougnet C, Lacroix L, Baudin E, Schlumberger M, Leboulleux S. Persistent disease and recurrence in differentiated thyroid cancer patients with undetectable postoperative stimulated thyroglobulin level. Endocr Relat Cancer. 2011 Mar 3;18(2):R29-40. doi: 10.1677/ERC-10-0292. Print, 2011 Apr. PMID:21183629 doi:http://dx.doi.org/10.1677/ERC-10-0292
  17. ↑ Torrigiani G, Doniach D, Roitt IM. Serum thyroglobulin levels in healthy subjects and in patients with thyroid disease. J Clin Endocrinol Metab. 1969 Mar;29(3):305-14. doi: 10.1210/jcem-29-3-305. PMID:5773064 doi:http://dx.doi.org/10.1210/jcem-29-3-305
  18. ↑ Pacini F, Lippi F, Formica N, Elisei R, Anelli S, Ceccarelli C, Pinchera A. Therapeutic doses of iodine-131 reveal undiagnosed metastases in thyroid cancer patients with detectable serum thyroglobulin levels. J Nucl Med. 1987 Dec;28(12):1888-91. PMID:3681445
  19. ↑ Morgenthaler NG, Froehlich J, Rendl J, Willnich M, Alonso C, Bergmann A, Reiners C. Technical evaluation of a new immunoradiometric and a new immunoluminometric assay for thyroglobulin. Clin Chem. 2002 Jul;48(7):1077-83. PMID:12089177
  20. ↑ Hughes DT, White ML, Miller BS, Gauger PG, Burney RE, Doherty GM. Influence of prophylactic central lymph node dissection on postoperative thyroglobulin levels and radioiodine treatment in papillary thyroid cancer. Surgery. 2010 Dec;148(6):1100-6; discussion 1006-7. doi:, 10.1016/j.surg.2010.09.019. PMID:21134539 doi:http://dx.doi.org/10.1016/j.surg.2010.09.019
  21. ↑ Galligan JP, Winship J, van Doorn T, Mortimer RH. A comparison of serum thyroglobulin measurements and whole body 131I scanning in the management of treated differentiated thyroid carcinoma. Aust N Z J Med. 1982 Aug;12(4):248-54. doi: 10.1111/j.1445-5994.1982.tb03805.x. PMID:6814409 doi:http://dx.doi.org/10.1111/j.1445-5994.1982.tb03805.x
  22. ↑ Flores-Rebollar A, Perez-Diaz I, Lagunas-Barcenas S, Garcia-Martinez B, Rivera-Moscoso R, Fagundo-Sierra R. Clinical utility of an ultrasensitive thyroglobulin assay in the follow-up of patients with differentiated thyroid cancer: can the stimulation test be avoided in patients with an intermediate recurrence risk? Acta Otorhinolaryngol Ital. 2018 Jun;38(3):188-193. doi: 10.14639/0392-100X-1494. PMID:29984794 doi:http://dx.doi.org/10.14639/0392-100X-1494
  23. ↑ Di Jeso B, Arvan P. Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology. Endocr Rev. 2016 Feb;37(1):2-36. doi: 10.1210/er.2015-1090. Epub 2015 Nov 23. PMID:26595189 doi:http://dx.doi.org/10.1210/er.2015-1090
  24. ↑ Kawasaki E, Yasui J, Tsurumaru M, Takashima H, Ikeoka T, Mori F, Akazawa S, Ueki I, Kobayashi M, Kuwahara H, Abiru N, Yamasaki H, Kawakami A. Sequential elevation of autoantibodies to thyroglobulin and glutamic acid decarboxylase in type 1 diabetes. World J Diabetes. 2013 Oct 15;4(5):227-30. doi: 10.4239/wjd.v4.i5.227. PMID:24147207 doi:http://dx.doi.org/10.4239/wjd.v4.i5.227
  25. ↑ Tomer Y, Greenberg DA, Concepcion E, Ban Y, Davies TF. Thyroglobulin is a thyroid specific gene for the familial autoimmune thyroid diseases. J Clin Endocrinol Metab. 2002 Jan;87(1):404-7. doi: 10.1210/jcem.87.1.8291. PMID:11788684 doi:http://dx.doi.org/10.1210/jcem.87.1.8291
  26. ↑ De Leo S, Pearce EN. Autoimmune thyroid disease during pregnancy. Lancet Diabetes Endocrinol. 2018 Jul;6(7):575-586. doi:, 10.1016/S2213-8587(17)30402-3. Epub 2017 Dec 12. PMID:29246752 doi:http://dx.doi.org/10.1016/S2213-8587(17)30402-3
  27. ↑ Katko M, Gazso AA, Hircsu I, Bhattoa HP, Molnar Z, Kovacs B, Andrasi D, Aranyosi J, Makai R, Veress L, Torok O, Bodor M, Samson L, Nagy EV. Thyroglobulin level at week 16 of pregnancy is superior to urinary iodine concentration in revealing preconceptual and first trimester iodine supply. Matern Child Nutr. 2018 Jan;14(1). doi: 10.1111/mcn.12470. Epub 2017 Jun 7. PMID:28593684 doi:http://dx.doi.org/10.1111/mcn.12470
  28. ↑ Matalon ST, Blank M, Levy Y, Carp HJ, Arad A, Burek L, Grunebaum E, Sherer Y, Ornoy A, Refetoff S, Weiss RE, Rose NR, Shoenfeld Y. The pathogenic role of anti-thyroglobulin antibody on pregnancy: evidence from an active immunization model in mice. Hum Reprod. 2003 May;18(5):1094-9. doi: 10.1093/humrep/deg210. PMID:12721190 doi:http://dx.doi.org/10.1093/humrep/deg210
  29. ↑ Heemstra KA, Liu YY, Stokkel M, Kievit J, Corssmit E, Pereira AM, Romijn JA, Smit JW. Serum thyroglobulin concentrations predict disease-free remission and death in differentiated thyroid carcinoma. Clin Endocrinol (Oxf). 2007 Jan;66(1):58-64. doi:, 10.1111/j.1365-2265.2006.02685.x. PMID:17201802 doi:http://dx.doi.org/10.1111/j.1365-2265.2006.02685.x
  30. ↑ Gerfo PL, Colacchio T, Colacchio D, Feind C. Thyroglobulin in benign and malignant thyroid disease. JAMA. 1979 Mar 2;241(9):923-4. PMID:762873
  31. ↑ Miyauchi A, Kudo T, Miya A, Kobayashi K, Ito Y, Takamura Y, Higashiyama T, Fukushima M, Kihara M, Inoue H, Tomoda C, Yabuta T, Masuoka H. Prognostic impact of serum thyroglobulin doubling-time under thyrotropin suppression in patients with papillary thyroid carcinoma who underwent total thyroidectomy. Thyroid. 2011 Jul;21(7):707-16. doi: 10.1089/thy.2010.0355. Epub 2011 Jun 7. PMID:21649472 doi:http://dx.doi.org/10.1089/thy.2010.0355
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