Overview
After translation, proteins are folded, sorted to their destinations, chemically modified and finally degraded. This topic covers sorting, folding, post-translational modifications such as phosphorylation, and degradation through ubiquitin and the proteasome.
Protein sorting and trafficking
Proteins undergo sorting, folding, modification, and degradation after translation.
Newly made proteins are directed to specific cellular destinations via sorting signals—short peptide sequences in the protein. There are three main sorting mechanisms:
- Gated Transport (to nucleus): Proteins with a nuclear localization signal (NLS) pass through the nuclear pore complex. NLS is not removed after import, enabling reuse after cell division.
- Transmembrane Transport (to mitochondria): Cytosolic proteins with an N-terminal signal peptide are guided by receptors and translocators into mitochondria in an unfolded state. The signal is cleaved inside.
- Vesicular Transport (to ER/Golgi/lysosomes/secretion): Proteins with an N-terminal ER signal are recognized by signal recognition particle (SRP) and translated directly into the ER lumen. They are then transported by vesicles to the Golgi, and from there to:
- Cell membrane (default secretion)
- Secretory vesicles (regulated, clathrin-coated)
- Lysosomes (via mannose-6-phosphate signal)
- Vesicle Coating:
- COPII: forms vesicles for transport from the ER to the Golgi
- COPI: forms vesicles for transport from the Golgi to the ER
I-cell Disease: Failure to add mannose-6-phosphate leads to misrouting of lysosomal enzymes, causing inclusion bodies and fatal childhood disease.
- Protein Sorting
- Directs proteins to specific cellular compartments.
- 3 Ways of Protein Transport:
- Gated Transport:
- For nuclear proteins, passing through nuclear pore complex.
- Transmembrane Transport:
- Proteins pushed through lipid bilayer.
- Vesicular Transport:
- Proteins enclosed in vesicles, traveling and fusing with organelles.
- Sorting of Nuclear Proteins:
- Nuclear pores allow gated transport of large molecules.
- Proteins with nuclear localization signals recognized and transported.
- Nuclear Localization Signals:
- Short peptide sequences retained in the nucleus.
- Mutations in these signals lead to cytoplasmic retention.
- Sorting of Mitochondrial Proteins:
- Long signal peptides direct proteins to mitochondria.
- Protease removes signal peptide after translocation.
- Sorting of Surface, Secreted, and Lysosome Proteins:
- Trafficked between endomembranes via export pathway.
- Export Pathway:
- Proteins synthesized on rER translocated to ER lumen.
- Vesicular transport to Golgi complex and destination (cell surface or lysosomes).
- Three Ways out of Golgi:
- Constitutive secretion, regulated secretion, and pathway to lysosomes.
- When Sorting of Lysosomes Fails:
- Mannose-6-phosphate deficiency leads to exocytosis instead of lysosomal targeting.
- Retrograde Trafficking from Endosome to Trans-Golgi Network:
- Endosomes sort cargo for lysosomal degradation or retrograde transport.
- 3 Ways out of Golgi:
- Constitutive Secretion:
- Default pathway for protein export.
- Regulated Secretion: