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M03.04.06 Translation and Protein Targeting: Ribosomes and the Rough Endoplasmic Reticulum
Translation, the process of protein synthesis from mRNA, begins on free ribosomes in the cytoplasm. However, not all proteins synthesized on these ribosomes remain in the cytoplasm. Some proteins are destined for specific locations such as the endoplasmic reticulum (ER), cell membrane, or lysosomes. The location of translation and the final destination of proteins are determined by specific signals within the protein structure.
Proteins Translated on Free Ribosomes
Proteins synthesized on free ribosomes remain in the cytoplasm or are transported to organelles like mitochondria. Some examples include:
- Cytoplasmic proteins include enzymes, structural proteins, and proteins involved in signal transduction.
- Mitochondrial proteins: Mitochondrial proteins encoded by nuclear genes are translated into the cytoplasm and then imported into mitochondria.
Proteins Translated on the Rough Endoplasmic Reticulum (RER)
Proteins destined for secretion, insertion into the cell membrane, or delivery to lysosomes are translated on ribosomes associated with the rough endoplasmic reticulum (RER). Examples include:
- Secreted proteins: Such as insulin and antibodies.
- Membrane proteins: Such as receptors and ion channels.
- Lysosomal enzymes: Enzymes involved in the degradation of cellular waste.
Molecular Chaperones and Proteasomes
Protein Folding and Molecular Chaperones
Protein folding is critical for function. Molecular chaperones assist newly synthesized proteins in achieving their proper conformation. Incorrectly folded proteins are marked for degradation. Chaperones function in various cellular compartments, including the cytoplasm and ER.
Proteasomes and Ubiquitin
Misfolded or damaged proteins are tagged with ubiquitin and degraded by the proteasome, a large cytoplasmic complex. This process not only prevents the accumulation of dysfunctional proteins but also generates peptide fragments for antigen presentation by MHC class I molecules.
Protein Targeting to Organelles
Proteins are directed to their specific cellular destinations by signal sequences:
- N-terminal hydrophobic signal sequence: Directs translation to the RER.
- Mannose-6-phosphate: Targets lysosomal enzymes to lysosomes.
Failure of proper targeting can result in diseases such as cystic fibrosis, where mutations interfere with protein folding and localization, leading to degradation by proteasomes instead of functioning in the membrane.
Clinical Correlates
Cystic Fibrosis
The most common cause of cystic fibrosis is the deletion of phenylalanine at position 508 (ΔF508) of the CFTR protein. This mutation disrupts proper folding, leading to the degradation of the protein by the proteasome instead of its translocation to the cell membrane, contributing to the disease pathology.
α1-Antitrypsin Deficiency
Mutations in α1-antitrypsin lead to protein misfolding, causing its accumulation in the ER and eventual damage to liver cells, resulting in conditions like cirrhosis.
I-Cell Disease
I-cell disease results from defective phosphorylation of lysosomal enzymes, causing them to be secreted outside the cell instead of being delivered to lysosomes. This leads to the accumulation of cellular waste, presenting as coarse facial features, joint immobility, and organ dysfunction.
Table: Protein Synthesis Locations and Targeting Signals
| Protein Type | Translation Site | Targeting Signal | Final Destination |
|---|---|---|---|
| Secreted proteins | Rough ER | N-terminal hydrophobic sequence | Extracellular environment |
| Membrane proteins | Rough ER | N-terminal hydrophobic sequence | Plasma membrane |
| Lysosomal enzymes | Rough ER | N-terminal sequence, Mannose-6-phosphate | Lysosomes |
| Cytoplasmic proteins | Free ribosomes | None | Cytoplasm |
| Mitochondrial proteins | Free ribosomes | Mitochondrial targeting sequence | Mitochondria |
Points to Remember
- Translation begins on free ribosomes, but the location and function of the protein dictate whether it remains in the cytoplasm or is targeted to organelles.
- Molecular chaperones assist in protein folding, while proteasomes degrade misfolded proteins.
- Diseases such as cystic fibrosis and I-cell disease result from protein folding or targeting failures.
Bibliography
- Lodish H, Berk A, Kaiser CA, et al. Molecular Cell Biology. 8th ed. W. H. Freeman; 2016.
- Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 6th ed. Garland Science; 2015.