Progressive quality control of secretory proteins in the early secretory compartment by ERp44.
Progressive quality control of secretory proteins in the early secretory compartment by ERp44.
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DOI：
10.1242/jcs.153239
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发表时间：
2014-10-01
影响因子：
4
通讯作者：
Sitia R
中科院分区：
文献类型：
--
作者：
Sannino S;Anelli T;Cortini M;Masui S;Degano M;Fagioli C;Inaba K;Sitia R
ERp 44是分泌途径的pH调节伴侣。在高尔基体的酸性环境中，其C-末端尾部改变构象，同时暴露用于货物捕获的底物结合位点和通过与同源受体的相互作用用于ER检索的RDEL基序。半胱氨酸29在活性位点的质子化允许在体外和体内的尾部运动。在这里，我们表明，也保守的组氨酸在C-末端尾巴调节ERp 44在体内。缺乏这些组氨酸的突变体在保留底物方面异常活跃。令人惊讶的是，它们也是O-糖基化的和部分分泌的。客户蛋白的共表达防止组氨酸突变体的分泌，迫使尾部打开和RDEL可及性。客户端诱导的RDEL暴露允许蛋白质从不同的站点检索沿着分泌途径，如通过O-糖基化模式的变化后，不同的合作伙伴的过度表达。随后的梯度可以帮助优化不同货物的折叠和组装。内源性ERp 44是O-糖基化和分泌的人原代子宫内膜细胞，这表明这些过程可能的病理生理作用。
ERp44 is a pH-regulated chaperone of the secretory pathway. In the acidic milieu of the Golgi, its C-terminal tail changes conformation, simultaneously exposing the substrate-binding site for cargo capture and the RDEL motif for ER retrieval via interactions with cognate receptors. Protonation of cysteine 29 in the active site allows tail movements in vitro and in vivo. Here we show that also conserved histidines in the C-terminal tail regulate ERp44 in vivo. Mutants lacking these histidines are hyperactive in retaining substrates. Surprisingly, they are also O-glycosylated and partially secreted. Co-expression of client proteins prevents secretion of the histidine mutants, forcing tail opening and RDEL accessibility. Client-induced RDEL exposure allows retrieval of proteins from distinct stations along the secretory pathway, as indicated by the changes in O-glycosylation patterns upon over-expression of different partners. The ensuing gradients may help optimising folding and assembly of different cargoes. Endogenous ERp44 is O-glycosylated and secreted by human primary endometrial cells, suggesting possible pathophysiological roles of these processes.
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影响因子：
4.8
作者：
Masui, Shoji;Vavassori, Stefano;Inaba, Kenji
通讯作者：
Inaba, Kenji
影响因子：
6.6
作者：
Otsu, Mieko;Bertoli, Gloria;Sitia, Roberto
通讯作者：
Sitia, Roberto
影响因子：
4.8
作者：
Swiatkowska, Maria;Padula, Gianluca;Cierniewski, Czeslaw S.
通讯作者：
Cierniewski, Czeslaw S.
影响因子：
16
作者：
Vavassori, Stefano;Cortini, Margherita;Masui, Shoji;Sannino, Sara;Anelli, Tiziana;Caserta, Imma R.;Fagioli, Claudio;Mossuto, Maria F.;Fornili, Arianna;van Anken, Eelco;Degano, Massimo;Inaba, Kenji;Sitia, Roberto
通讯作者：
Sitia, Roberto
影响因子：
11.4
作者：
Anelli, T;Alessio, M;Sitia, R
通讯作者：
Sitia, R