Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER.
Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER.
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DOI：
10.1083/jcb.200204122
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发表时间：
2002-07-22
期刊：
影响因子：
--
通讯作者：
Paganetti P
中科院分区：
文献类型：
--
作者：
Molinari M;Galli C;Piccaluga V;Pieren M;Paganetti P
BACE 457是最近鉴定的人β-分泌酶的胰腺同种型。我们报告说，这种膜糖蛋白及其可溶性变体的特点是在ER折叠效率低下，导致蛋白酶体介导的ER相关降解（ERAD）。降解过程的解剖显示，从钙连接蛋白释放后，广泛氧化的BACE 457在解折叠和移位到细胞溶质中进行降解之前瞬时进入与内腔分子伴侣BiP和蛋白质二硫键异构酶（PDI）相关的二硫键结合的复合物中。BACE 457及其内腔变体在ER内腔中以二硫键结合的复合物积累，也是在蛋白质降解被抑制时。分解复合物，并在降解机制再活化后从ER中清除错误折叠的多肽。我们的数据提供了新的见解ERAD的机制，显示了顺序参与的钙连接蛋白和BiP/PDI分子伴侣系统。我们报告了意想不到的瞬时形成的共价复合物在ER腔ERAD过程中，我们表明，PDI参与作为一种氧化还原酶和氧化还原驱动的伴侣蛋白的制备从哺乳动物ER的降解。
BACE457 is a recently identified pancreatic isoform of human β-secretase. We report that this membrane glycoprotein and its soluble variant are characterized by inefficient folding in the ER, leading to proteasome-mediated ER-associated degradation (ERAD). Dissection of the degradation process revealed that upon release from calnexin, extensively oxidized BACE457 transiently entered in disulfide-bonded complexes associated with the lumenal chaperones BiP and protein disulfide isomerase (PDI) before unfolding and dislocation into the cytosol for degradation. BACE457 and its lumenal variant accumulated in disulfide-bonded complexes, in the ER lumen, also when protein degradation was inhibited. The complexes were disassembled and the misfolded polypeptides were cleared from the ER upon reactivation of the degradation machinery. Our data offer new insights into the mechanism of ERAD by showing a sequential involvement of the calnexin and BiP/PDI chaperone systems. We report the unexpected transient formation of covalent complexes in the ER lumen during the ERAD process, and we show that PDI participates as an oxidoreductase and a redox-driven chaperone in the preparation of proteins for degradation from the mammalian ER.
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DOI：
10.1073/pnas.92.5.1764
发表时间：
1995-02-28
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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影响因子：
7.8
作者：
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