Protein Import to Endoplasmic Reticulum
PROTEINS FOR IMPORT
• Water-soluble proteins
• Transmembrane proteins
KEY MECHANISMS
• Cotranslational: ribosomes continue synthesizing protein as it crosses membrane
• Post-translational: protein imports after it is completely synthesized by cytosolic ribosomes
SIGNAL SEQUENCE
• Hydrophobic sequence (15-60 residues): directs proteins to specific organelles (i.e. ER membrane)
COTRANSLATIONAL IMPORT OF WATER-SOLUBLE PROTEINS
1. SRP (signal recognition particle) recognizes and binds signal sequence on a nascent protein in the cytosol; halts translation
2. SRP (with ribosomal complex) binds SRP receptor
3. SRP released from complex
4. Signal sequence inserts into translocon, translocon opens and translation resumes
5. Signal peptidase cleaves signal sequence and releases protein in ER lumen
6. Chaperones help protein fold correctly
POST-TRANSLATIONAL IMPORT OF WATER-SOLUBLE PROTEINS
1. Chaperones maintain newly synthesized protein's unfolded conformation in cytosol
2. Translocon/SRP receptor complex recognizes signal sequence
3. Protein enters translocon; chaperone in lumen prevents peptide from sliding back through translocon
CLINICAL CORRELATION
Alzheimer's and Parkinson's
• Neurodegenerative diseases that involve improper folding of proteins in endoplasmic reticulum