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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.

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.

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.

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.

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.

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.

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.