Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors
Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors
复制标题
DOI：
10.1210/me.2003-0406
复制
发表时间：
2004-07-01
影响因子：
--
通讯作者：
Segaloff, DL
中科院分区：
文献类型：
--
作者：
Mizrachi, D;Segaloff, DL
已发现糖蛋白激素受体的大多数功能丧失突变是由于受体的错误折叠，导致其细胞内滞留，从而降低细胞表面表达。内质网内的伴侣蛋白在促进新合成的蛋白质的折叠以及识别和分离错误折叠的蛋白质中起重要作用，从而防止它们转运到高尔基体。本研究开始阐明伴侣蛋白在糖蛋白激素受体及其错误折叠突变体折叠中的作用。为此，我们研究了钙连接蛋白，钙网蛋白，Grp94，BiP，ERp57和蛋白质二硫键异构酶与三种糖蛋白激素受体的潜在关联。钙连接蛋白、钙网蛋白和蛋白质二硫键异构酶被发现与所有三种野生型（wt）糖蛋白激素受体的不成熟形式相关。作为错误折叠的糖蛋白激素受体的例子，我们研究了两个人LH受体（hLHR）功能丧失突变体，我们显示主要是作为保留在细胞内的不成熟形式表达。值得注意的是，与错误折叠的hLHR突变体的伴侣蛋白协会的模式与野生型hLHR观察到的不同。此外，出乎意料的是，发现两种错误折叠的hLHR突变体之间的伴侣蛋白结合存在差异。总之，我们的研究表明，尽管三种野生型糖蛋白激素受体使用相同的伴侣蛋白，但不同的伴侣蛋白与其错误折叠的突变体相关，并且相互作用的特异性在突变体之间可以变化，最有可能反映它们在被靶向降解之前实现的不同折叠阶段。
Most loss-of-function mutations of the glycoprotein hormone receptors have been found to be due to the misfolding of the receptor, resulting in its intracellular retention and, therefore, decreased cell surface expression. Chaperone proteins within the endoplasmic reticulum play an essential role in facilitating the folding of newly synthesized proteins and in recognizing and segregating misfolded proteins, thereby preventing their transit to the Golgi. The present study was conducted to begin to elucidate the role of chaperone proteins in the folding of the glycoprotein hormone receptors and misfolded mutants thereof. Toward this end, we examined the potential associations of calnexin, calreticulin, Grp94, BiP, ERp57, and protein disulfide-isomerase with each of the three glycoprotein hormone receptors. Calnexin, calreticulin, and protein disulfide-isomerase were found to associate with the immature forms of all three wild-type (wt) glycoprotein hormone receptors. As examples of misfolded glycoprotein hormone receptors, we studied two human LH receptor (hLHR) loss-of-function mutants that we show to be expressed predominantly as immature forms that are retained intracellularly. Significantly, the patterns of chaperone protein associations with the misfolded hLHR mutants differ from that observed with the wt hLHR. Furthermore, and unexpectedly, the chaperone protein associations were found to differ between the two misfolded hLHR mutants. Altogether, our studies show that although the same chaperone proteins are used by the three wt glycoprotein hormone receptors, different chaperone proteins associate with misfolded mutants thereof, and the specificity of interactions can vary between mutants, most likely reflecting the different stages of folding they achieve before being targeted for degradation.