Directing Proteins to the Rough Endoplasmic Reticulum

The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can finally be embedded in the cell membranes.

Structure of the ER Signal Sequence

The protein signal sequences in eukaryotes and prokaryotes have a typical architecture. For example, the ER signal sequences have a positively charged N-terminal region followed by a central, hydrophobic region and polar amino acid residues at the C-terminal end. In addition, a cleavage site at the C-terminal of the signal sequence helps to remove the signal peptide from the mature protein.

Signal Recognition Particle and its Receptor

The signal recognition particle (SRP) is a riboprotein complex. In mammals, the SRP comprises six polypeptides and a 7S RNA molecule. The signal sequence binding pocket of the SRP is lined by methionines, which have unbranched, flexible side chains that help to effectively accommodate the hydrophobic regions of the signal sequences with different amino acid compositions. Despite the flexibility, the binding of SRP with the correct protein cargo intended to be delivered to rough ER adds a fidelity check for binding with the SRP receptor. The GTP-linked SRP and SRP receptor form a heterodimer and complete two functional, active sites for GTP hydrolysis in both the interacting partners. The GTP hydrolysis is crucial for the delivery and unloading of the ribosomes at the rough ER membranes and the release of the signal sequence by the SRP.

Ribosome Recycling

The ribosome units assembled for protein synthesis in the cytosol are structurally and functionally identical to those present on the rough ER. The ER signal sequence of a nascent polypeptide recruits it and the attached ribosomes to the rough ER membrane from the cytosolic pool. After translation, the ribosome units are released back to the cytosol. Therefore, there is the recycling of the ribosome particles between ER and the cytosol.