Defective Protein Folding and Intracellular Retention of Thyroglobulin-R19K Mutant as a Cause of Human Congenital Goiter
| العنوان: | Defective Protein Folding and Intracellular Retention of Thyroglobulin-R19K Mutant as a Cause of Human Congenital Goiter |
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| المؤلفون: | Piyanuch Jongsamak, Jaemin Lee, Peter Arvan, Bhinyo Panijpan, Shaikh Abu Hossain, Paul S. Kim, Bailing Li, Jin Ho Bae, Shekar Menon |
| المصدر: | Molecular Endocrinology. 22:477-484 |
| بيانات النشر: | The Endocrine Society, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Protein Folding, Calnexin, Leupeptins, Blotting, Western, Mutant, Protein Disulfide-Isomerases, Golgi Apparatus, Biology, Arginine, Endoplasmic Reticulum, Thyroglobulin, Article, Mice, symbols.namesake, Alkaloids, Endocrinology, Chlorocebus aethiops, Animals, Humans, Immunoprecipitation, Missense mutation, Secretion, Protein disulfide-isomerase, Endoplasmic Reticulum Chaperone BiP, Molecular Biology, Heat-Shock Proteins, Goiter, Lysine, Point mutation, Endoplasmic reticulum, Biological Transport, General Medicine, Golgi apparatus, Molecular biology, Amino Acid Substitution, COS Cells, Mutation, symbols, Electrophoresis, Polyacrylamide Gel, Molecular Chaperones, Protein Binding, Signal Transduction |
| الوصف: | It has been suggested that a thyroglobulin (Tg)-R19K missense mutation may be a newly identified cause of human congenital goiter, which is surprising for this seemingly conservative substitution. Here, we have examined the intracellular fate of recombinant mutant Tg expressed in COS-7 cells. Incorporation of the R19K mutation largely blocked Tg secretion, and this mutant was approximately 90% degraded intracellularly over a 24-h period after synthesis. Before its degradation, the Tg-R19K mutant exhibited abnormally increased association with molecular chaperones BiP, calnexin, and protein disulfide isomerase, and was unable to undergo anterograde advance from the endoplasmic reticulum (ER) through the Golgi complex. Inhibitors of proteasomal proteolysis and ER mannosidase-I both prevented ER-associated degradation of the Tg-R19K mutant and increased its association with ER molecular chaperones. ER quality control around Tg residue 19 is not dependent upon charge but upon side-chain packing, because Tg-R19Q was efficiently secreted. Whereas a Tg mutant truncated after residue 174 folds sufficiently well to escape ER quality control, introduction of the R19K point mutation blocked its secretion. The data indicate that the R19K mutation induces local misfolding in the amino-terminal domain of Tg that has global effects on Tg transport and thyroid hormonogenesis. |
| تدمد: | 1944-9917 0888-8809 |
| DOI: | 10.1210/me.2007-0183 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::afeea80ac0261cc89d4c1cb0a9f4304b https://doi.org/10.1210/me.2007-0183 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....afeea80ac0261cc89d4c1cb0a9f4304b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19449917 08888809 |
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| DOI: | 10.1210/me.2007-0183 |