Furin-mediated processing in the early secretory pathway: Sequential cleavage and degradation of misfolded insulin receptors
Furin-mediated processing in the early secretory pathway: Sequential cleavage and degradation of misfolded insulin receptors
复制标题
DOI：
10.1073/pnas.97.22.11905
复制
发表时间：
2000-10-24
影响因子：
11.1
通讯作者：
Steiner, DF
中科院分区：
文献类型：
--
作者：
Bass, J;Turck, C;Steiner, DF
不正确折叠的膜蛋白被保留在内质网中，然后通过分子伴侣和细胞内蛋白酶的网络转向降解途径。在这里，我们报告了保留在早期分泌途径中的突变胰岛素前受体（Pro（62））在枯草杆菌蛋白酶样蛋白酶furin（SPC 1）的四碱基共有位点处进行蛋白水解切割，产生两种80/120 kDa的不稳定的蛋白水解中间体，对应于α *（135 kDa）和β *（90 kDa）亚基。它们比未裂解的前受体蛋白降解得更快。正常RKRR加工位点的定点诱变防止切割。使用抑制剂和弗林蛋白酶缺陷的细胞系证实，弗林蛋白酶是负责前受体裂解;弗林蛋白酶过表达增加了突变体，但不是野生型受体的降解。总之，这些结果表明，加工和降解顺序发生突变体前受体。
Improperly folded membrane proteins are retained in the endoplasmic reticulum and then diverted to a degradative pathway by a network of molecular chaperones and intracellular proteases, Here we report that mutant insulin proreceptors (Pro(62)) retained in the early secretory pathway undergo proteolytic cleavage at a tetrabasic concensus site for the subtilisin-like protease furin (SPC 1), generating two unstable proteolytic intermediates of 80/120 kDa corresponding to alpha>(*) over bar * (135 kDa) and beta (90 kDa) subunits. These are degraded more rapidly than the uncleaved proreceptor protein. Site-directed mutagenesis of the normal RKRR processing site prevented cleavage. Use of inhibitors and furin-deficient cell lines confirmed that furin is responsible for proreceptor cleavage; furin overexpression increased the degradation of mutant but not wildtype receptors. Together, these results suggest that processing and degradation occur sequentially for mutant proreceptors.