15.6
共翻译蛋白易位
蛋白质跨膜易位是一个古老的过程，即使在细菌和古细菌中也会发生。事实上，在原核生物和真核生物之间，易位机制的组成部分仍然是保守的。
共翻译易位中的 Sec61 通道伙伴
在共翻译易位过程中，Sec61 通道伙伴能够与信号识别颗粒（SRP）、信号识别颗粒受体 (SR) 和核糖体进行合作，从而将新生多肽链…
大多数蛋白质在合成过程中即进入内质网腔，这一过程称为共翻译转运。
首先，携带核糖体-新生肽链复合物的信号识别颗粒（SRP）-SRP受体复合物将该复合物卸载到Sec61通道上。
当核糖体与通道对齐后，多肽链N端的信号序列会结合到信号序列识别位点上。
随着翻译的继续， 多肽链形成一个环状结构，推动打开通道堵塞物，进入内质网腔。
当多肽链进入腔内时，信号序列通过Sec61通道的侧向门孔进入相邻的信号肽酶复合物，并在此被切除。
当蛋白质被动进入内质网腔时，通道插头保持打开状态。
蛋白质完全转位至腔内后，通道阻断蛋白会反弹以阻止其返回胞质溶胶。
在内质网腔内，定位于内质网的分子伴侣（如 BiP）会立即结合已转位的蛋白质，并协助其进行蛋白质折叠。
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Q1: What is cotranslational protein translocation and how does it differ from other translocation methods?
Cotranslational protein translocation occurs while proteins are still being synthesized by ribosomes. The nascent polypeptide chain enters the ER lumen during translation, contrasting with post-translational translocation of proteins to the RER, where proteins are fully synthesized before translocation. This simultaneous synthesis and translocation process is mediated by the SRP-SRP receptor complex and the Sec61 channel.
Q2: How does the Sec61 channel facilitate protein entry into the ER lumen?
The Sec61 channel contains a plug that blocks the channel opening. When the signal sequence of the nascent polypeptide latches onto a recognition site, it pushes the plug open, creating an entry pathway. As translation continues, the polypeptide descends passively through the channel into the ER lumen. After translocation completes, the channel plug bounces back to seal the channel and prevent protein return to the cytosol.
Q3: What role does the signal sequence play in cotranslational translocation?
The signal sequence at the N-terminal of the nascent polypeptide chain recognizes and latches onto a specific signal sequence recognition site on the Sec61 channel. This interaction triggers channel opening and initiates translocation. The signal sequence then exits through the lateral gate of the Sec61 channel to enter the signal peptidase complex, where it is cleaved off during translocation.
Q4: What are the key protein components that work with the Sec61 channel during cotranslational translocation?
The signal recognition particle (SRP) and SRP receptor (SR) deliver the ribosome-nascent chain complex to the Sec61 channel through GTP hydrolysis. Accessory proteins like the translocon-associated protein (TRAP) complex stabilize weak signal sequences, while the TRAM protein acts as a chaperone assisting in folding and membrane integration of translocating proteins.
Q5: How do ribosomes contribute to protein movement through the Sec61 channel?
Ribosomes act as primary translocation motors, pushing the nascent polypeptide chain toward the ER lumen during translation elongation. The ribosome aligns with the Sec61 channel, and as peptide bonds form, the growing polypeptide is propelled through the channel. This process requires no additional energy beyond the GTP hydrolysis used for normal peptide chain elongation.
Q6: What happens to proteins after they complete translocation into the ER lumen?
Once the polypeptide fully enters the ER lumen, the Sec61 channel plug closes to prevent protein return to the cytosol. Resident ER chaperones, particularly BiP, immediately bind the translocated protein and assist in proper protein folding. This quality control mechanism ensures proteins achieve their correct three-dimensional structure within the ER environment.
Q7: Why is the TRAP complex essential for proteins with low-hydrophobicity signal sequences?
The TRAP complex is a substrate-specific auxiliary component that stabilizes signal sequences with weak hydrophobic interactions. It directly interacts with the Sec61 channel and maintains the channel in an open conformation, compensating for the reduced binding strength between the signal sequence and the channel. This ensures secure anchoring and successful translocation of these challenging substrates.