A pH-regulated quality control cycle for surveillance of secretory protein assembly.
A pH-regulated quality control cycle for surveillance of secretory protein assembly.
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DOI：
10.1016/j.molcel.2013.04.016
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发表时间：
2013-06-27
期刊：
影响因子：
16
通讯作者：
Sitia, Roberto
中科院分区：
文献类型：
--
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
为了保证分泌蛋白质组的质量，严格的控制系统在内质网（ER）-高尔基体界面上运行，防止非天然产物的释放。被认为正确折叠的不完全组装的寡聚蛋白质必须依赖于专用于正确组装的额外质量控制机制。在这里，我们揭示了ERp 44如何在cisGolgi和ER之间循环，以pH调节的方式，巡逻二硫键连接的寡聚体，如IgM和脂联素的组装。在中性、ER-等效pH下，ERp 44羧基末端尾封闭底物结合位点。在cisGolgi的较低pH下，这种肽的构象重排，可能涉及ERp 44的活性半胱氨酸的质子化，同时暴露底物结合位点和−RDEL基序，允许捕获孤儿分泌蛋白亚基和通过KDEL受体的ER检索。ERp 44组装控制循环将钙连接蛋白/钙网蛋白下游的分泌保真度和效率与BiP依赖性质量控制循环相结合。ERp 44在早期分泌途径中控制pH调节的组装控制循环ERp 44的活性位点和-RDEL ER回收基序的可接近性是pH依赖性ERp 44的活性位点的解蔽可能涉及半胱氨酸29的质子化ERp 44在cisGolgi-等效pH下捕获客户蛋白以回收到ER
To warrant the quality of the secretory proteome, stringent control systems operate at the endoplasmic reticulum (ER)-Golgi interface, preventing the release of nonnative products. Incompletely assembled oligomeric proteins that are deemed correctly folded must rely on additional quality control mechanisms dedicated to proper assembly. Here we unveil how ERp44 cycles between cisGolgi and ER in a pH-regulated manner, patrolling assembly of disulfide-linked oligomers such as IgM and adiponectin. At neutral, ER-equivalent pH, the ERp44 carboxy-terminal tail occludes the substrate-binding site. At the lower pH of the cisGolgi, conformational rearrangements of this peptide, likely involving protonation of ERp44’s active cysteine, simultaneously unmask the substrate binding site and −RDEL motif, allowing capture of orphan secretory protein subunits and ER retrieval via KDEL receptors. The ERp44 assembly control cycle couples secretion fidelity and efficiency downstream of the calnexin/calreticulin and BiP-dependent quality control cycles. ERp44 governs a pH-regulated assembly control cycle in the early secretory pathway Accessibility of ERp44’s active site and –RDEL ER retrieval motif is pH dependent Unmasking of ERp44’s active site likely involves protonation of cysteine 29 ERp44 captures client proteins at cisGolgi-equivalent pH for retrieval to the ER
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影响因子：
4.8
作者：
Appenzeller-Herzog, C;Roche, AC;Hauri, HP
通讯作者：
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影响因子：
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通讯作者：
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