How are the nascent secretory proteins targeted to the ER?

The targeting of nascent secretory proteins to the endoplasmic reticulum (ER) is a highly coordinated and essential process in eukaryotic cells, especially for proteins that are destined to be secreted outside the cell or localized to membranes and organelles of the endomembrane system. This entire process occurs co-translationally, meaning that the protein is directed to the ER while it is still being synthesized by the ribosome.

This mechanism follows a specific pathway called the Signal Hypothesis, first proposed by Gunter Blobel, which explains how newly forming proteins are recognized and directed to the ER membrane. The process includes five essential steps, which are explained in detail below:

1. Signal Sequence Recognition

Nascent secretory proteins contain a special amino acid stretch called the signal peptide or signal sequence at their N-terminal end. This signal sequence is typically 15–30 amino acids long and contains a hydrophobic core that is recognized as the "tag" for targeting. As the protein is being synthesized on a free cytosolic ribosome, the signal sequence emerges from the ribosome tunnel first.

2. Binding of Signal Recognition Particle (SRP)

The signal sequence is recognized and bound by a Signal Recognition Particle (SRP), a ribonucleoprotein complex made of six proteins and one 7S RNA molecule. SRP temporarily halts further translation, preventing premature folding of the protein and allowing the complex to be guided to the ER.

3. SRP-Ribosome Docking to ER Membrane

The SRP-nascent chain-ribosome complex docks to the SRP receptor, which is located on the cytosolic face of the rough ER membrane. This interaction is GTP-dependent, and both SRP and SRP receptor have GTPase activity.

4. Transfer to the Translocon

Once docking is complete, the ribosome is transferred to a protein-conducting channel in the ER membrane known as the translocon (mainly formed by the Sec61 complex). SRP is released and translation resumes. The growing polypeptide is then threaded into the ER lumen through this translocon channel.

5. Cleavage of Signal Sequence and Folding

As the protein enters the ER, the signal sequence is usually cleaved off by an enzyme called signal peptidase. The protein then undergoes proper folding with the help of ER-resident chaperones such as BiP and may receive post-translational modifications like glycosylation.










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