Down-regulation of cell surface receptors is modulated by polar residues within the transmembrane domain.
Down-regulation of cell surface receptors is modulated by polar residues within the transmembrane domain.
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细胞表面受体的下调由跨膜域内的极性残基调节。
DOI：
10.1091/mbc.11.8.2643
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发表时间：
2000
影响因子：
3.3
通讯作者：
Collawn,JF
中科院分区：
文献类型：
--
作者：
Zaliauskiene,L;Kang,S;Brouillette,CG;Lebowitz,J;Arani,RB;Collawn,JF
回收受体如何与内体中下调的受体分离尚不清楚。在以前的研究中，我们证明了转铁蛋白受体（TR）跨膜结构域（TM）中的取代将蛋白质从有效回收受体转化为快速下调的受体。在这项研究中，我们证明，“信号”内的TM必要和足够的下调是Thr11Gln17Thr19（编号TM）。将这些极性残基移植到野生型TR中促进受体下调，这可以通过蛋白质半衰期和受体再循环的变化来证明。令人惊讶的是，这种修饰也显著增加了TR内化率（增加了约79%）。蔗糖梯度离心和交联研究表明，受体的自我关联倾向与下调相关。有趣的是，一些含有TM极性残基的细胞表面蛋白被认为是有效的下调，而回收受体的低密度脂蛋白和转铁蛋白明显缺乏这些残基。因此，我们的数据表明，一个简单的模型中，TM序列内的特定残基显着影响胞吞作用后的膜蛋白的命运，提供了一个替代信号的受体复合物的下调，充分表征的细胞质尾靶向信号。
How recycling receptors are segregated from down-regulated receptors in the endosome is unknown. In previous studies, we demonstrated that substitutions in the transferrin receptor (TR) transmembrane domain (TM) convert the protein from an efficiently recycling receptor to one that is rapidly down regulated. In this study, we demonstrate that the “signal” within the TM necessary and sufficient for down-regulation is Thr11Gln17Thr19(numbering in TM). Transplantation of these polar residues into the wild-type TR promotes receptor down-regulation that can be demonstrated by changes in protein half-life and in receptor recycling. Surprisingly, this modification dramatically increases the TR internalization rate as well (∼79% increase). Sucrose gradient centrifugation and cross-linking studies reveal that propensity of the receptors to self-associate correlates with down-regulation. Interestingly, a number of cell surface proteins that contain TM polar residues are known to be efficiently down-regulated, whereas recycling receptors for low-density lipoprotein and transferrin conspicuously lack these residues. Our data, therefore, suggest a simple model in which specific residues within the TM sequences dramatically influence the fate of membrane proteins after endocytosis, providing an alternative signal for down-regulation of receptor complexes to the well-characterized cytoplasmic tail targeting signals.