De la Vieja Antonio, Ginter Christopher S, Carrasco Nancy
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Mol Endocrinol. 2005 Nov;19(11):2847-58. doi: 10.1210/me.2005-0162. Epub 2005 Jun 23.
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 A3) at this position, suggesting that G543 is in a tightly packed region of NIS.
钠/碘同向转运体（NIS）是一种关键的膜糖蛋白，介导甲状腺及其他组织中的碘主动转运。在分离出编码NIS的cDNA后，已鉴定出10种导致先天性碘转运缺陷的NIS突变。其中三种突变（T354P、G395R和Q267E）已在分子水平上得到充分表征。所有三种NIS突变蛋白均能正确靶向质膜；然而，Q267E显示出最低活性，而T354P和G395R则无活性。在此，我们表明，与这些突变体不同，G543E NIS仅部分成熟并保留在细胞内；因此，它不能正确靶向细胞表面，这显然是由于错误折叠所致。这些发现表明，G543残基在NIS成熟和运输中起重要作用。值得注意的是，通过在该位置进行小的中性氨基酸取代（体积<129 Å3）可挽救NIS活性，这表明G543位于NIS的紧密堆积区域。
