Signal sequences encode information for protein folding in the endoplasmic reticulum.
Signal sequences encode information for protein folding in the endoplasmic reticulum.
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信号序列编码内质网中蛋白质折叠的信息。
DOI：
10.1083/jcb.202203070
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发表时间：
2023-01-02
期刊：
影响因子：
--
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Sun等人的研究表明，具有微疏水信号序列的蛋白质在进入内质网的过程中会在Sec61转座子处暂停，需要Sec63/BiP来克服这种暂停，促进内质网中随后的蛋白质折叠，从而防止在BiP缺乏时蛋白质聚集。哺乳动物中三分之一的新合成蛋白通过Sec61易位转运到内质网（ER）。蛋白质易位如何与内质网中的伴侣蛋白可用性协调以促进蛋白质折叠尚不清楚。我们发现，微疏水信号序列和跨膜结构域会导致Sec61易位的短暂滞留，并且需要管腔BiP伴侣来进行有效的蛋白质易位。使用底物捕获蛋白质组学方法，我们发现新生蛋白携带轻度疏水信号序列积聚在Sec61转座子的细胞质侧。Sec63被共翻译招募到易位位点，并介导BiP与传入多肽的结合。BiP结合不仅释放易位暂停的新生链，而且确保内质网中的蛋白质折叠。增加信号序列的疏水性绕过了依赖于Sec63/BiP的易位，但易位蛋白在有限的BiP可用性下容易在内质网中错误折叠和聚集。因此，信号序列引导的蛋白质折叠可以解释为什么信号序列是多样的，并使用多种蛋白质易位途径。
Sun et al. show that proteins with marginally hydrophobic signal sequences pause at the Sec61 translocon on their way into the ER and require Sec63/BiP to overcome the pause and facilitate subsequent protein folding in the ER, which prevents protein aggregation during BiP deficiency. One-third of newly synthesized proteins in mammals are translocated into the endoplasmic reticulum (ER) through the Sec61 translocon. How protein translocation coordinates with chaperone availability in the ER to promote protein folding remains unclear. We find that marginally hydrophobic signal sequences and transmembrane domains cause transient retention at the Sec61 translocon and require the luminal BiP chaperone for efficient protein translocation. Using a substrate-trapping proteomic approach, we identify that nascent proteins bearing marginally hydrophobic signal sequences accumulate on the cytosolic side of the Sec61 translocon. Sec63 is co-translationally recruited to the translocation site and mediates BiP binding to incoming polypeptides. BiP binding not only releases translocationally paused nascent chains but also ensures protein folding in the ER. Increasing hydrophobicity of signal sequences bypasses Sec63/BiP-dependent translocation, but translocated proteins are prone to misfold and aggregate in the ER under limited BiP availability. Thus, the signal sequence–guided protein folding may explain why signal sequences are diverse and use multiple protein translocation pathways.
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影响因子：
16
作者：
Feigel, Matthias J.;Hendershot, Linda M.
通讯作者：
Hendershot, Linda M.
BIP介导的分子机制的内质网的Sec61易位门控。
DOI：
10.1083/jcb.200409174
发表时间：
2005-01-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Alder NN;Shen Y;Brodsky JL;Hendershot LM;Johnson AE
通讯作者：
Johnson AE
DOI：
10.1016/j.bbamcr.2013.03.007
发表时间：
2013-11
影响因子：
5.1
作者：
Gidalevitz, Tali;Stevens, Fred;Argon, Yair
通讯作者：
Argon, Yair
影响因子：
19
作者：
Helenius, Ari;Marquardt, Thorsten;Braakman, Ineke
通讯作者：
Braakman, Ineke
影响因子：
8.8
作者：
Haßdenteufel S;Johnson N;Paton AW;Paton JC;High S;Zimmermann R
通讯作者：
Zimmermann R