ArticleThe Journal of clinical investigation2008
The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone.
Article in The Journal of clinical investigation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 73 citations in OpenAlex.
- Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.Signal transduction and targeted therapy · 2026Review
- Identification of protein precursor for thyroid hormone synthesis in basal chordate ascidian Styela clava.Nature communications · 2026Article
- Molecular recognition of thyroglobulin by sortilin.Nature communications · 2026Article
- Public Cohort Analysis Identifies Thyroglobulin Variants as Hypothyroidism Risk Factors.bioRxiv : the preprint server for biology · 2025Article
- A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion.International journal of molecular sciences · 2025Article
- Identification of southern Taiwan genetic variants in thyroid dyshormonogenesis through whole-exome sequencing.The Kaohsiung journal of medical sciences · 2024Article
- Clinical and molecular study of patients with thyroid dyshormogenesis and variants in theFrontiers in endocrinology · 2024Article
- Structural features of thyroglobulin linked to protein trafficking.Protein science : a publication of the Protein Society · 2023Article
- The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.Endocrine · 2023Article
- Defective Thyroglobulin: Cell Biology of Disease.International journal of molecular sciences · 2022Review
- Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect.International journal of molecular sciences · 2022Article
- A glance at post-translational modifications of human thyroglobulin: potential impact on function and pathogenesis.European thyroid journal · 2022Review
- A Novel Mutation in the Thyroglobulin Gene Resulting in Neonatal Goiter and Congenital Hypothyroidism in an Eritrean InfantJournal of clinical research in pediatric endocrinology · 2022Article
- Cryo-EM structure of native human thyroglobulin.Nature communications · 2022Article
- Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death.JCI insight · 2021Article
- Thyroglobulin Interactome Profiling Defines Altered Proteostasis Topology Associated With Thyroid Dyshormonogenesis.Molecular & cellular proteomics : MCP · 2021Article
- Next-Generation Sequencing Analysis Reveals Frequent Familial Origin and Oligogenism in Congenital Hypothyroidism With Dyshormonogenesis.Frontiers in endocrinology · 2021Article
- The Pervasive Effects of ER Stress on a Typical Endocrine Cell: Dedifferentiation, Mesenchymal Shift and Antioxidant Response in the Thyrocyte.Frontiers in endocrinology · 2020Article
- Lessons from animal models of endocrine disorders caused by defects of protein folding in the secretory pathway.Molecular and cellular endocrinology · 2020Review
- The role of thyroglobulin in thyroid hormonogenesis.Nature reviews. Endocrinology · 2019Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Thyroid hormonogenesis requires secretion of thyroglobulin, a protein comprising Cys-rich regions I, II, and III (referred to collectively as region I-II-III) followed by a cholinesterase-like (ChEL) domain. Secretion of mature thyroglobulin requires extensive folding and glycosylation in the ER. Multiple reports have linked mutations in the ChEL domain to congenital hypothyroidism in humans and rodents; these mutations block thyroglobulin from exiting the ER and induce ER stress. We report that, in a cell-based system, mutations in the ChEL domain impaired folding of thyroglobulin region I-II-III. Truncated thyroglobulin devoid of the ChEL domain was incompetent for cellular export; however, a recombinant ChEL protein ("secretory ChEL") was secreted efficiently. Coexpression of secretory ChEL with truncated thyroglobulin increased intracellular folding, promoted oxidative maturation, and facilitated secretion of region I-II-III, indicating that the ChEL domain may function as an intramolecular chaperone. Additionally, we found that the I-II-III peptide was cosecreted and physically associated with secretory ChEL. A functional ChEL domain engineered to be retained intracellularly triggered oxidative maturation of I-II-III but coretained I-II-III, indicating that the ChEL domain may also function as a molecular escort. These insights into the role of the ChEL domain may represent potential therapeutic targets in the treatment of congenital hypothyroidism.
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Registered trials
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