Cryo-EM: A new dawn in thyroid biology

Coscia, Francesca; Taler‐Verčič, Ajda

doi:10.1016/j.mce.2021.111309

Cited by 4 publications

(4 citation statements)

References 117 publications

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“…chaperones, receptors and proteases) ( 7 ). After many years of research, the structure of human Tg has been recently resolved by cryo-EM ( 9 , 24 ). The primary structure of Tg is composed of 17 repeated cysteine-rich repeats alternated with linker regions and followed by a dimeric acetylcholine esterase-like domain (AChE or C-terminal domain, CTD) ( 7 , 25 , 26 ).…”

Section: Up To Date With Thyroglobulin Structure Domains Dimerisation...mentioning

confidence: 99%

“…Today, despite the Tg assembly being finally uncovered, the role of the conserved domain architecture in the hormonogenesis cycle is yet to be revealed. However, the integration of biochemical and cellular studies, guided by the knowledge of the Tg dimeric assembly, promises to soon unveil these important mysteries in Tg function ( 19 , 24 , 34 ).…”

Section: Up To Date With Thyroglobulin Structure Domains Dimerisation...mentioning

confidence: 99%

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A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis

Tosatto

Coscia

2022

European Thyroid Journal

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Thyroid hormones are essential for the metabolism of vertebrates and their synthesis, storage and release in the thyroid gland are orchestrated by their large protein precursor thyroglobulin (Tg). Alterations of Tg structure and localisation often correlate with major thyroid disorders. Namely, Tg is a main antigen in auto-immune thyroid diseases and mutations in its gene are one of the causes of congenital hypothyroidism. Post-translational modifications (PTMs) are crucial for Tg surface properties and may be affected by disease microenvironment, yet their role in thyroid homeostasis and pathogenesis remains elusive. The advance of electron cryo-microscopy (cryo-EM) has recently enabled the structure of Tg to be revealed in the un-iodinated and iodinated states. Moreover, ad hoc proteomic analyses have lately identified new PTMs in Tg. Here, we provide an overview of the Tg cryo-EM models obtained so far, and we build a three-dimensional map of known PTMs in Tg. Based on their location, we suggest potential implication of each PTM in hormonogenesis, interactions with cellular partners, colloid cross-linking and hormone release. In addition, several PTMs overlap with immunogenic regions and pathogenic gene mutations. Hence, our analysis reveals a possible cross-talk between PTMs and alteration of Tg function in these disorders. In perspective, multi- omics analyses from patients, interpreted with structural and functional data, may generate more robust models to correlate phenotypes with classes of Tg functional alterations. This integrative approach will likely provide more targeted strategies to restore specific Tg functions in different thyroid pathologies.

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Section: Up To Date With Thyroglobulin Structure Domains Dimerisation...mentioning

confidence: 99%

Section: Up To Date With Thyroglobulin Structure Domains Dimerisation...mentioning

confidence: 99%

A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis

Tosatto

Coscia

2022

European Thyroid Journal

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“…The main function of the thyroid gland is the production of the thyroid hormones (TH) 3,3',5-triiodo-L-thyronine (T3) and 3,3',5,5'-tetraiodo-L-thyronine (T4), which are involved in fundamental regulatory processes in the body. To do so, the thyroid gland synthesizes TH on the backbone of thyroglobulin (Tg), liberates these upon sequential Tg proteolysis, and releases them into the bloodstream (Brix et al 2019, Coscia & Taler-Verčič 2021. Tg solubilization and utilization is initiated in the thyroid follicle lumen and continues within endocytic compartments, mediated by proteases such as endolysosomal cathepsins (Friedrichs et al 2003, Jordans et al 2009.…”

Section: Introductionmentioning

confidence: 99%

Lack of L-type amino acid transporter 2 in murine thyroid tissue induces autophagy

Venugopalan

Rehders

Weber

et al. 2023

Journal of Molecular Endocrinology

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Proteolytic cleavage of thyroglobulin (Tg) for thyroid hormone (TH) liberation is followed by TH release from thyroid follicles into the circulation, enabled by TH transporters. The existence of a functional link between Tg-processing cathepsin proteases and TH transporters has been shown to be independent of the hypothalamus-pituitary-thyroid axis. Thus, lack of cathepsin K, combined with genetic defects in the TH transporters Mct8 and Mct10, i.e. the Ctsk‑/-/Mct8-/y/Mct10-/- genotype, results in persistent Tg proteolysis due to autophagy induction. Because amino acid transport by L-type amino acid transporter 2 (Lat2) has been described to regulate autophagy, we asked whether Lat2 availability is affected in Ctsk‑/-/Mct8-/y/Mct10-/- thyroid glands. Our data revealed that while mRNA amounts and sub-cellular localization of Lat2 remained unaltered in thyroid tissue of Ctsk‑/-/Mct8-/y/Mct10-/- mice in comparison to wild-type (WT) controls, the Lat2 protein amounts were significantly reduced. These data suggest a direct link between Lat2 function and autophagy induction in Ctsk‑/-/Mct8-/y/Mct10‑/‑ mice. Indeed, thyroid tissue of Lat2-/- mice showed enhanced endo-lysosomal cathepsin activities, increased autophagosome formation, and enhanced autophagic flux. Collectively, these results suggest a mechanistic link between insufficient Lat2 protein function and autophagy induction in the thyroid gland of male mice.

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“…Papillary thyroid carcinoma (PTC) is a malignant and life-threatening cancer, the incidence of which has increased sharply in recent years. Most patients have significant prognostic effects after surgical treatment, with a 10-year survival rate of more than 90%, but the prevention and treatment of PTC remains an important challenge (1). In the past few years, the American Thyroid Association (ATA) has recommended total thyroidectomy as the primary treatment for PTC larger than 1 cm (2).…”

Section: Introductionmentioning

confidence: 99%

Correlation between parathyroid function and serum levels of 1,25(OH)2D3, serum phosphorus, and parathyroid hormone after surgery for papillary thyroid carcinoma

Bo Wang,

Lei Gu,

Jun Liu

2023

Cell Mol Biol (Noisy-le-grand)

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Cryo-EM: A new dawn in thyroid biology

Cited by 4 publications

References 117 publications

A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis

A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis

Lack of L-type amino acid transporter 2 in murine thyroid tissue induces autophagy

Correlation between parathyroid function and serum levels of 1,25(OH)2D3, serum phosphorus, and parathyroid hormone after surgery for papillary thyroid carcinoma

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