Protein Sorting and Targeting in Eukaryotic Cells

Protein Sorting and Targeting in Eukaryotic Cells

• Protein sorting and targeting involve complex processes due to the internal organization of eukaryotic cells.
• The first step of protein sorting occurs during translation, while the polypeptide chain is still being synthesized.

Targeting Proteins to the Endoplasmic Reticulum

• In mammalian cells, most proteins enter the ER co-translationally, whereas in yeast, both co-translational and post-translational pathways are used.
• The amino acid sequence of the polypeptide chain being synthesized targets ribosomes for binding to the ER membrane.
• Signal sequences, typically 15-40 amino acids long, including 7-12 hydrophobic residues, are recognized and bound by the signal recognition particle (SRP).
• The SRP binds the ribosome, mRNA, and growing polypeptide chain, inhibiting further translation and targeting the complex to the rough ER.

Co-Translational Pathway

• The SRP binds to the SRP receptor on the ER membrane, triggering the hydrolysis of GTP bound to the SRP, releasing the SRP from the ribosome and signal sequence.
• The ribosome then binds to a protein translocation complex or translocon in the ER membrane, and the signal sequence is inserted into a membrane channel.
• The growing polypeptide chain is transferred through the translocon as translation proceeds, and the signal sequence is cleaved by signal peptidase.

Insertion of Proteins into the ER Membrane

• Proteins destined for the plasma membrane or membranes of compartments are initially inserted into the ER membrane instead of being released into the lumen.
• Integral membrane proteins are embedded in the membrane by hydrophobic sequences that span the phospholipid bilayer.
• The membrane-spanning portions of these proteins are usually α-helical regions consisting of 20-25 hydrophobic amino acids.
• The hydrophobic transmembrane α helix signals a change in the translocon, causing the membrane-spanning helices of the translocon to open and allowing the hydrophobic transmembrane domain of the protein to exit the translocon laterally.