The RXR-type endoplasmic reticulum-retention/retrieval signal of GABAB1 requires distant spacing from the membrane to function
The RXR-type endoplasmic reticulum-retention/retrieval signal of GABAB1 requires distant spacing from the membrane to function
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DOI：
10.1124/mol.104.010256
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发表时间：
2005-07-01
影响因子：
3.6
通讯作者：
Bettler, B
中科院分区：
文献类型：
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作者：
Gassmann, M;Haller, C;Bettler, B
功能性γ-氨基丁酸B型（GABA（B））受体通常仅在GABA（B1）与GABA（B2）亚基共表达时观察到。一个C-末端的腺嘌呤为基础的内质网（ER）保留/检索信号，RSRR，防止逃逸的未组装的GABA（B1）亚基从ER和限制表面表达正确组装的异聚体受体。GABA（B1）中的RSRR信号被GABA（B1）与GABA（B2）亚基的C-末端卷曲螺旋相互作用屏蔽。在这里，我们研究了GABA（B1）中的RSRR基序在移植到异位位点时是否仍然具有功能。我们发现，GABA（B1）中的RSRR信号在三个细胞内环中的任何一个都是无活性的，但在C-末端尾的远端区域内移动时仍然具有功能。将RSRR信号定位在更靠近质膜的C末端缺失显著降低了其有效性，支持了接近膜限制了对RSRR基序的访问。GABA（B1）中的功能性异位RSRR信号在卷曲螺旋二聚化不存在的情况下被GABA（B2）亚基有效灭活，支持卷曲螺旋相互作用对于受体复合物从ER释放并不关键。这些数据是一致的模型中，从其活性区，而不是其直接屏蔽卷曲螺旋二聚体RSRR去除触发向前贩运。因为RXR类型的基于精氨酸的细胞内滞留信号（其中X代表任何氨基酸）用于调节几种多聚体复合物的组装和表面转运，所以这种机制也可以应用于其他蛋白质。
Functional gamma-aminobutyric acid type B (GABA(B)) receptors are normally only observed upon coexpression of GABA(B1) with GABA(B2) subunits. A C-terminal arginine-based endoplasmic reticulum ( ER) retention/retrieval signal, RSRR, prevents escape of unassembled GABA(B1) subunits from the ER and restricts surface expression to correctly assembled heteromeric receptors. The RSRR signal in GABA(B1) is proposed to be shielded by C-terminal coiled-coil interaction of the GABA(B1) with the GABA(B2) subunit. Here, we investigated whether the RSRR motif in GABA(B1) remains functional when grafted to ectopic sites. We found that the RSRR signal in GABA(B1) is inactive in any of the three intracellular loops but remains functional when moved within the distal zone of the C-terminal tail. C-terminal deletions that position the RSRR signal closer to the plasma membrane drastically reduce its effectiveness, supporting that proximity to the membrane restricts access to the RSRR motif. Functional ectopic RSRR signals in GABA(B1) are efficiently inactivated by the GABA(B2) subunit in the absence of coiled-coil dimerization, supporting that coiled-coil interaction is not critical for release of the receptor complex from the ER. The data are consistent with a model in which removal of RSRR from its active zone rather than its direct shielding by coiled-coil dimerization triggers forward trafficking. Because arginine-based intracellular retention signals of the type RXR, where X represents any amino acid, are used to regulate assembly and surface transport of several multimeric complexes, such a mechanism may apply to other proteins as well.