Thyroid follicular epithelial cells produce and release thyroglobulin (Tg) which is a large glycoprotein dimer that acts as a precursor scaffold for thyroid hormones triiodothyronine (T3) and thyroxine (T4). Hormonally active T3 and T4 residues become embedded within the Tg backbone through these reactions. Thyroid hormone homeostasis relies on this regulated process because it plays a vital role in metabolic functions as well as growth and development.
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Mechanisms of Thyroglobulin-Related Diseases
Genetic mutations alongside abnormal protein expression and autoimmunity or post-translational modification defects lead to diseases related to Thyroglobulin (Tg). The synthesis and storage or secretion of thyroid hormones face disruption from various mechanisms that subsequently produce different thyroid diseases.
TG Gene Mutations
Mutations in the TG gene disrupt Tg synthesis and folding while also blocking its secretion which results in congenital hypothyroidism. Mutations in the TG gene can cause retention of misfolded Tg within the endoplasmic reticulum while impairing both iodination and conjugation processes which result in loss-of-function mutations.
Autoimmune Thyroid Disease
Tg serves as a self-antigen during autoimmune disease processes. The presence of anti-thyroglobulin antibodies together with lymphocyte infiltration triggers thyroid destruction which results in hypothyroidism.
Fig 1. Physiological function of Thyroglobulin (Tosatto, L., et al. 2021).
Role of Thyroglobulin in Thyroid Hormone Homeostasis
Thyroglobulin (Tg) functions as the principal protein responsible for thyroid hormone production and is essential for maintaining thyroid hormone equilibrium in the body. T3 (triiodothyronine) and T4 (thyroxine) use thyroglobulin as their precursor transporter. The protein Tg holds multiple tyrosine residues that undergo iodination to generate monoiodotyrosine (MIT) and diiodotyrosine (DIT). The MIT molecule combines with either one DIT or two DIT molecules to produce T3 and T4 which remain connected to the Tg molecule.
T3 and T4 remain linked to Tg through covalent bonds while stored in the follicular lumen until endocytosis enables their release. Tg undergoes endocytosis to enter follicular cells where lysosomal proteases break it down and release T3 and T4 into the bloodstream. Thyroid stimulating hormone controls the function of this process. The rate of thyroid hormone production depends on both the Tg concentration and its extent of iodination. Structural abnormalities or mutations affecting Tg result in thyroid hormone synthesis disorders and can trigger congenital hypothyroidism among other thyroid diseases.
Overview of Post-translational Modifications of Thyroglobulin
The Golgi apparatus and endoplasmic reticulum perform essential post-translational modifications on Tg for proper folding and secretion while enabling its iodination activity and immune recognition. As Tg's main modification type within the endoplasmic reticulum occurs through N-linked glycosylation. The protein displays 16 to 20 N-glycosylation sites which support proper folding and stability while also regulating protein quality control during transport and secretion. When glycosylation deviates from normal patterns it alters protein structure and function which can lead to endoplasmic reticulum stress. Tg function depends heavily on the iodination of its tyrosine residues. The formation of MIT and DIT stands as an essential step in the synthesis process of T3 and T4 hormones.
Glycosylation
Multiple glycosylation sites exist on thyroglobulin protein where oligosaccharide chains attach themselves. Glycosylation modifies protein stability and solubility while controlling cell recognition and signal transduction pathways.
Hydroxylation
Proline and lysine amino acids undergo hydroxylation modifications which maintain protein stability and structure.
Phosphorylation
Although researchers study thyroglobulin phosphorylation less frequently than other modifications this change affects both the protein's activity and signaling capability.
Sulfation
The protein undergoes sulfation on certain parts which leads to biological activity and cellular interaction capabilities.
Disulfide Bond Formation
The three-dimensional structure of thyroglobulin stays stable because cysteine residues form disulfide bonds which are essential for its function.
Thyroglobulin Participates in Regulation of Physiological Activities
The synthesis and storage of thyroid hormones alongside their release depend on thyroglobulin which maintains thyroid hormone homeostasis. The operation of diseases related to thyroglobulin functions through various elements including immune system reactions and tumor marker expression which influence thyroid activity control. Medical professionals take a comprehensive approach to these factors when diagnosing and treating patients.
Thyroglobulin biological functions including thyroid hormone synthesis and release together with transport and storage mechanisms are dependent on its post-translational modifications. Thyroid-related diseases research requires thorough understanding of these modifications because they play a critical role in thyroid tumors, hyperthyroidism and hypothyroidism studies.
References
- Tosatto, L., et al. A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis. European Thyroid Journal. 2022, 11(3).
- Adaixo, R., et al. Cryo-EM structure of native human thyroglobulin. Nature communications. 2022, 13(1): 61.
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