Mercken L, Simons M J, Swillens S, Massaer M, Vassart G
Nature. 1985;316(6029):647-51. doi: 10.1038/316647a0.
In mammals, an adequate supply of thyroid hormones is essential for normal growth and neurological development. The biosynthesis of thyroid hormones involves an iodinated precursor protein, thyroglobulin, which may be considered an extreme example of a pro-hormone. Thyroglobulin is a dimeric glycoprotein of relative molecular mass (Mr) 660,000 (660K), which is secreted by the thyrocyte and stored in the lumen of the thyroid follicle. The hormonogenic reaction is extracellular, and involves iodination of tyrosyl residues of thyroglobulin and the intramolecular coupling of a subset of these into thyroxine (T4) and triiodothyronine (T3), which remain part of the polypeptide chain. Secretion of hormones results from the endocytosis of thyroglobulin followed by its complete hydrolysis in lysosomes. Considering that the maximum yield of hormones is approximately 6-8 per 660K protein, the whole process is apparently wasteful. However, the efficiency of thyroglobulin as a thyroid hormone precursor is extremely high when the supply of iodine is short; in such conditions, almost all the iodine incorporated is found in iodothyronine. Hence it is suggested that the thyroglobulin structure has evolved to allow for the preferential and efficient iodination and coupling of the hormonogenic tyrosines. Here we report the complete primary structure of bovine thyroglobulin, derived from the sequence of its 8,431-base-pair complementary DNA. The 2,769-amino-acid sequence is characterized by a pattern of imperfect repeats derived from three cysteine-rich motifs. Four hormonogenic tyrosines have been precisely localized near the amino and carboxyl ends of the protein.
在哺乳动物中，充足的甲状腺激素供应对于正常生长和神经发育至关重要。甲状腺激素的生物合成涉及一种碘化前体蛋白——甲状腺球蛋白，它可被视为激素原的一个极端例子。甲状腺球蛋白是一种相对分子质量（Mr）为660,000（660K）的二聚体糖蛋白，由甲状腺细胞分泌并储存于甲状腺滤泡腔中。激素生成反应发生在细胞外，包括甲状腺球蛋白酪氨酸残基的碘化以及这些残基中一部分在分子内偶联形成甲状腺素（T4）和三碘甲状腺原氨酸（T3），它们仍为多肽链的一部分。激素的分泌源于甲状腺球蛋白的内吞作用，随后在溶酶体中完全水解。鉴于每660K蛋白质的激素最大产量约为6 - 8个，整个过程显然较为浪费。然而，当碘供应短缺时，甲状腺球蛋白作为甲状腺激素前体的效率极高；在这种情况下，几乎所有掺入的碘都存在于碘甲状腺原氨酸中。因此，有人提出甲状腺球蛋白的结构已经进化，以允许激素生成酪氨酸优先且高效地碘化和偶联。在此，我们报告了源自其8431个碱基对互补DNA序列的牛甲状腺球蛋白的完整一级结构。2769个氨基酸的序列具有由三个富含半胱氨酸的基序衍生而来的不完全重复模式。四个激素生成酪氨酸已被精确地定位在该蛋白质的氨基端和羧基端附近。
