| RRC ID |
2816
|
| 著者 |
Menon S, Lee J, Abplanalp WA, Yoo SE, Agui T, Furudate S, Kim PS, Arvan P.
|
| タイトル |
Oxidoreductase interactions include a role for ERp72 engagement with mutant thyroglobulin from the rdw/rdw rat dwarf.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
Newly synthesized thyroglobulin (Tg), the secretory glycoprotein that serves as precursor in thyroid hormone synthesis, normally forms transient covalent protein complexes with oxidoreductases of the endoplasmic reticulum (ER). The Tg-G2320R mutation is responsible for congenital hypothyroidism in rdw/rdw rats, in which a lack of secondary thyroid enlargement (goiter) implicates death of thyrocytes as part of disease pathogenesis. We found that mutant Tg-G2320R was retained within the ER with no detectable synthesis of thyroxine, had persistent exposure of free cysteine thiols, and was associated with activated ER stress response but incomplete ER-associated degradation (ERAD). Tg-G2320R associated with multiple ER resident proteins, most notably ERp72, including covalent Tg-ERp72 interactions. In PC Cl3 thyrocytes, inducible overexpression of ERp72 increased the ability of cells to maintain Tg cysteines in a reduced state. Noncovalent interactions of several ER chaperones with newly synthesized Tg-G2320R diminished over time in parallel with ERAD of the mutant protein, yet a small ERAD-resistant Tg fraction remained engaged in covalent association with ERp72 even 2 days post-synthesis. Such covalent protein aggregates may set the stage for apoptotic thyrocyte cell death, preventing thyroid goiter formation in rdw/rdw rats.
|
| 巻・号 |
282(9)
|
| ページ |
6183-91
|
| 公開日 |
2007-3-2
|
| DOI |
10.1074/jbc.M608863200
|
| PII |
S0021-9258(20)52226-6
|
| PMID |
17200118
|
| PMC |
PMC2542443
|
| MeSH |
Animals
Apoptosis
Dwarfism / etiology*
Dwarfism / metabolism
Endoplasmic Reticulum
Goiter
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Mutation, Missense
Oxidoreductases / metabolism*
Protein Binding
Protein Transport
Rats
Rats, Mutant Strains
Thyroglobulin / genetics*
Thyroglobulin / metabolism
Thyroid Gland / cytology
|
| IF |
4.238
|
| 引用数 |
35
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ラット |
F344.WIC-Tgrdw/Kts(strainID=1037) |
