Molecular analysis of a congenital iodide transport defect:: G543E impairs maturation and trafficking of the Na+/I- symporter
Molecular analysis of a congenital iodide transport defect:: G543E impairs maturation and trafficking of the Na+/I- symporter
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DOI：
10.1210/me.2005-0162
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发表时间：
2005-11-01
影响因子：
--
通讯作者：
Carrasco, N
中科院分区：
文献类型：
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作者：
De la Vieja, A;Ginter, CS;Carrasco, N
Na+/I-转运体(NIS)是一种关键的膜糖蛋白，在甲状腺和其他组织中介导主动的I-转运。在分离编码NIS的cDNA后，已鉴定出10个导致先天性碘转运缺陷的NIS突变。这些突变中的三个(T354P、G395R和Q267E)已经在分子水平上得到了彻底的表征。所有三个NIS突变蛋白都正确地靶向质膜；然而，Q267E显示出最低的活性，而T354P和G395R则没有活性。在这里，我们证明了与这些突变体相比，G543E NIS只部分成熟，并被保留在细胞内；因此，它不能正确地靶向细胞表面，显然是由于折叠错误。这些发现表明，G543残基在NIS的成熟和贩运中起着重要作用。值得注意的是，NIS活性被该位置的小的中性氨基酸取代(体积129埃(3))所挽救，这表明G543处于NIS的紧密堆积区域。
The Na+/I- symporter (NIS) is a key membrane glycoprotein that mediates active I- transport in the thyroid and other tissues. Upon isolation of the cDNA encoding NIS, 10 NIS mutations that cause congenital iodide transport defect have been identified. Three of these mutations (T354P, G395R, and Q267E) have been thoroughly characterized at the molecular level. All three NIS mutant proteins are correctly targeted to the plasma membrane; however, whereas Q267E displays minimal activity, T354P and G395R are inactive. Here, we show that in contrast to these mutants, G543E NIS matures only partially and is retained intracellularly; thus, it is not targeted properly to the cell surface, apparently because of faulty folding. These findings indicate that the G543 residue plays significant roles in NIS maturation and trafficking. Remarkably, NIS activity was rescued by small neutral amino acid substitutions ( volume < 129 angstrom(3)) at this position, suggesting that G543 is in a tightly packed region of NIS.