Chaperone-Mediated Sec61 Channel Gating during ER Import of Small Precursor Proteins Overcomes Sec61 Inhibitor-Reinforced Energy Barrier.
Chaperone-Mediated Sec61 Channel Gating during ER Import of Small Precursor Proteins Overcomes Sec61 Inhibitor-Reinforced Energy Barrier.
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DOI：
10.1016/j.celrep.2018.03.122
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发表时间：
2018-05-01
期刊：
影响因子：
8.8
通讯作者：
Zimmermann R
中科院分区：
文献类型：
--
作者：
Haßdenteufel S;Johnson N;Paton AW;Paton JC;High S;Zimmermann R
蛋白质转运至哺乳动物内质网 (ER) 是由异三聚体 Sec61 通道介导的。信号识别颗粒 (SRP) 和 TRC 系统以及 Sec62 均被定性为小前分泌蛋白的膜靶向成分，而 Sec63 和腔内伴侣 BiP 则充当辅助易位成分。在这里，我们报告了两种天然的小前分泌蛋白和在特定 ER 成分耗尽后使用半透化人类细胞的工程变体的运输要求。我们的结果表明，hSnd2、Sec62、SRP 和 TRC 受体各自为短分泌蛋白提供替代靶向途径，并定义了 Sec63 和 BiP 在膜易位过程中的作用规则。我们发现 Sec62/Sec63 复合物加上 BiP 可以促进 Sec61 通道开放，从而允许具有弱信号肽或其他抑制特征的前体易位。 Sec61 抑制剂可以模拟 BiP 耗尽对 Sec61 门控的影响，表明它们都在相同的基本膜易位步骤中起作用。小人类前分泌蛋白使用所有已知的 Sec61 复合物靶向途径 BiP、Sec62 和 Sec63 选择性促进它们插入 Sec61 选择性由弱信号肽和下游抑制特征驱动 环状七缩肽表型 BiP 耗尽对 Sec61 门控的影响 蛋白质转运到人内质网 (ER) 是由异三聚体 Sec61 通道介导的。哈斯登特费尔等人。绘制短分泌前蛋白内质网导入中不同靶向途径和 Sec61 通道不同辅助成分需求的决定因素。前体多肽的不同特征决定了每个组分的结合。
Protein transport into the mammalian endoplasmic reticulum (ER) is mediated by the heterotrimeric Sec61 channel. The signal recognition particle (SRP) and TRC systems and Sec62 have all been characterized as membrane-targeting components for small presecretory proteins, whereas Sec63 and the lumenal chaperone BiP act as auxiliary translocation components. Here, we report the transport requirements of two natural, small presecretory proteins and engineered variants using semipermeabilized human cells after the depletion of specific ER components. Our results suggest that hSnd2, Sec62, and SRP and TRC receptor each provide alternative targeting pathways for short secretory proteins and define rules of engagement for the actions of Sec63 and BiP during their membrane translocation. We find that the Sec62/Sec63 complex plus BiP can facilitate Sec61 channel opening, thereby allowing precursors that have weak signal peptides or other inhibitory features to translocate. A Sec61 inhibitor can mimic the effect of BiP depletion on Sec61 gating, suggesting that they both act at the same essential membrane translocation step. Small human presecretory proteins use all known targeting routes to the Sec61 complex Their insertion into Sec61 is selectively facilitated by BiP, Sec62, and Sec63 Selectivity is driven by weak signal peptides plus downstream inhibitory features Cyclic heptadepsipeptides phenocopy the effect of BiP depletion on Sec61 gating Protein transport into the human endoplasmic reticulum (ER) is mediated by the heterotrimeric Sec61 channel. Haßdenteufel et al. map the determinants for requirement of different targeting pathways and different auxiliary components of the Sec61 channel in ER import of short presecretory proteins. Different characteristics of precursor polypeptides dictate the engagement of each component.
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影响因子：
3.3
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Müller L;de Escauriaza MD;Lajoie P;Theis M;Jung M;Müller A;Burgard C;Greiner M;Snapp EL;Dudek J;Zimmermann R
通讯作者：
Zimmermann R
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