Revisiting Iodination Sites in Thyroglobulin with an Organ-oriented Shotgun Strategy
Open accessAbstract
Thyroglobulin (Tg) is secreted by thyroid epithelial cells. It is essential for thyroid hormonogenesis and iodine storage. Although studied for many years, only indirect and partial surveys of its post-translational modifications were reported. Here, we present a direct proteomic approach, used to study the degree of iodination of mouse Tg without any preliminary purification. A comprehensive coverage of Tg was obtained using a combination of different proteases, MS/MS fragmentation procedures with inclusion lists and a hybrid mass high-resolution LTQ-Orbitrap XL mass spectrometer. Although only 16 iodinated sites are currently known for human Tg, we uncovered 37 iodinated tyrosine residues, most of them being mono- or diiodinated. We report the specific isotopic pattern of thyroxine modification, not recognized as a normal peptide pattern. Four hormonogenic sites were detected. Two donor sites were identified through the detection of a pyruvic acid residue in place of the initial tyrosine. Evidence for polypeptide cleavages sites due to the action of cathepsins and dipeptidyl proteases in the thyroid were also detected. This work shows that semi-quantitation of Tg iodination states is feasible for human biopsies and should be of significant medical interest for further characterization of human thyroid pathologies.
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Mass spectrometry analyses of thyroid-extracted TG have identified four or more acceptor tyrosines, but the position of the donors has remained unclear.
“Mass spectrometry analyses of thyroid-extracted TG have identified four or more acceptor tyrosines, but the position of the donors has remained unclear13.”
From The structure of human thyroglobulin (2020) · cites this paper as [13]
The Identification of Iodination Sites section identifies four distinct T3 or T4 acceptor positions: Tyr 25, 993, 1310, and 2572. But the Fate of the Lost Side Chain section identifies two donor positions, Tyr 259 and Tyr 2539, so the claim that donor positions remained unclear does not describe this study's findings. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the context of the thyroid gland and the iodine cycle in vertebrates, TG's structure effectively combines hormonogenesis with iodination of many other solvent exposed tyrosine residues for iodine storage.
“However, in the context of the thyroid gland and the iodine cycle in vertebrates, TG's structure effectively combines hormonogenesis with iodination of many other solvent exposed tyrosine residues for iodine storage21,13.”
From The structure of human thyroglobulin (2020) · cites this paper as [13]
The Abstract describes Tg as both a scaffold for thyroid hormonogenesis and an iodine reservoir. The Discussion reports many iodinated tyrosines but only a few hormonogenic sites, and suggests that the additional iodination probably stores iodine. The paper does not establish that those other residues are solvent-exposed; its direct findings are from mouse Tg rather than vertebrates generally. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredWhen all acceptors (Y24, Y2573, Y2766 and Y1310) were mutated, no T4 synthesis was observed, demonstrating that there are no more than four significant hormonogenic sites in TG.
“As shown in Figure 2c, when we mutated all acceptors (Y24, Y2573, Y2766 and Y1310)21,13 we observed no T4 synthesis, demonstrating that there are no more than four significant hormonogenic sites in TG.”
From The structure of human thyroglobulin (2020) · cites this paper as [13]
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The structure of human thyroglobulin
Coscia, F., Taler-Verčič, A., Chang, V. T., Sinn, L., O’Reilly, F. J., Izoré, T., Renko, M., Berger, I., Rappsilber, J., Turk, D., et al. (2020) · Nature · doi:10.1038/s41586-020-1995-4 · Cited by 147 · see citing works
- Authors
- Dedieu, A., Gaillard, J.-C., Pourcher, T., Darrouzet, E., & Armengaud, J.
- Affiliations
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Corresponding author
- Dedieu, Alain
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 286
- Issue
- 1
- Pages
- 259-269
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3012983
- OpenAlex
- W2011171468
- Cited by
- 53
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 1
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- thyroglobulin, tyrosine iodination, thyroxine, thyroid hormone synthesis, post-translational modification, thyroid biopsy
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Cathepsins, Hormones, Molecular Sequence Data, Protein Processing, Post-Translational, Thyroglobulin, Thyroid Gland, Tissue Extracts, Proteomics, Mice, Tandem Mass Spectrometry, Halogenation
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