Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding
Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding
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DOI：
10.1242/jcs.02651
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发表时间：
2005-11-15
影响因子：
4
通讯作者：
Bu, GJ
中科院分区：
文献类型：
--
作者：
Li, YH;Chen, JL;Bu, GJ
Wnt共受体LRP 5和LRP 6是低密度脂蛋白受体家族的两个成员。受体相关蛋白是低密度脂蛋白受体家族成员的特异性分子伴侣，也是一种普遍的拮抗剂。在这里，我们测试是否Mesd，低密度脂蛋白受体家族成员的新鉴定的伴侣，也结合到成熟的受体在细胞表面和拮抗配体结合。我们发现Mesd与细胞表面LRP 5和LRP 6结合，但不与低密度脂蛋白受体家族的其他成员结合。Scatchard分析显示，Mesd以高亲和力结合细胞表面LRP 6（K-d类似于3.3 nM）。有趣的是，Mesd的C-末端区域（在无脊椎动物的序列中不存在）对于与成熟LRP 6结合是必要的和足够的，并且对于LRP 6折叠是必需的。我们还发现，LRP 6不是一个组成型活性的内吞受体和受体相关蛋白的结合LRP 6部分竞争美司德结合。最后，我们证明了Mesd拮抗配体在细胞表面与LRP 6的结合。总之，我们的结果表明，除了作为一个折叠伴侣，Mesd可以作为一个受体拮抗剂抑制配体结合成熟LRP 6。
Wnt co-receptors LRP5 and LRP6 are two members of the low-density lipoprotein receptor family. Receptor-associated protein is not only a specialized chaperone but also a universal antagonist for members of the low-density lipoprotein receptor family. Here we test whether Mesd, a newly identified chaperone for members of the low-density lipoprotein receptor family, also binds to mature receptors at the cell surface and antagonizes ligand binding. We found that Mesd binds to cell surface LRP5 and LRP6, but not to other members of the low-density lipoprotein receptor family. Scatchard analysis revealed that Mesd binds cell surface LRP6 with high affinity (K-d similar to 3.3 nM). Interestingly, the C-terminal region of Mesd, which is absent in sequences from invertebrates, is necessary and sufficient for binding to mature LRP6, and is required for LRP6 folding. We also found that LRP6 is not a constitutively active endocytosis receptor and binding of the receptor-associated protein to LRP6 partially competes for Mesd binding. Finally, we demonstrated that Mesd antagonizes ligand binding to LRP6 at the cell surface. Together our results show that in addition to serving as a folding chaperone, Mesd can function as a receptor antagonist by inhibiting ligand binding to mature LRP6.