Protein degradation involves breaking down proteins into smaller peptides and amino acids through various cellular mechanisms. The two main pathways are lysosomal degradation and non-lysosomal degradation (primarily the ubiquitin-proteasome system).
1. Lysosomal Degradation (Autophagy)
This pathway involves the lysosome, an organelle containing various enzymes that can degrade proteins.
Steps:
-
Uptake into Lysosome (Autophagy): This is how the target proteins get to the lysosome. There are a few ways this can happen:
- Macroautophagy: Formation of a double-membrane vesicle called an autophagosome around the target protein(s) or organelle(s) within the cytoplasm. This autophagosome then fuses with a lysosome.
- Microautophagy: Direct engulfment of cytoplasmic components by the lysosome membrane.
- Chaperone-mediated autophagy (CMA): Selective targeting of proteins with a specific targeting motif to the lysosome, mediated by chaperone proteins.
-
Enzymatic Degradation: Once inside the lysosome, various proteases (e.g., cathepsins) degrade the proteins into amino acids and smaller peptides. These products are then transported out of the lysosome and back into the cytoplasm for reuse.
- Example: Degradation of damaged mitochondria via mitophagy (a type of macroautophagy).
2. Non-Lysosomal Degradation (Ubiquitin-Proteasome System)
This pathway involves the proteasome, a large protein complex that degrades ubiquitinated proteins.
Steps:
-
Tagging of Protein (Ubiquitination): The target protein is tagged with ubiquitin, a small regulatory protein. This process typically involves a cascade of enzymes:
- E1 (Ubiquitin-activating enzyme): Activates ubiquitin.
- E2 (Ubiquitin-conjugating enzyme): Carries ubiquitin.
- E3 (Ubiquitin ligase): Recognizes the target protein and transfers ubiquitin to it. E3 ligases confer substrate specificity.
- Multiple ubiquitin molecules are often added to form a polyubiquitin chain, which serves as a signal for degradation.
-
Recognition by Proteasome: The 26S proteasome recognizes the polyubiquitinated protein.
-
Deubiquitination and Unfolding: Before degradation, ubiquitin molecules are removed (deubiquitination) by deubiquitinating enzymes (DUBs), and the protein is unfolded.
-
Entry into the Proteasome Core: The unfolded protein enters the 20S core particle of the proteasome.
-
Proteolysis: Within the 20S core, proteases (specifically, trypsin-like, chymotrypsin-like, and caspase-like activities) degrade the protein into short peptides.
-
Release of Peptides: The short peptides are released from the proteasome and further degraded into amino acids by cytoplasmic peptidases.
- Example: Degradation of misfolded proteins or short-lived regulatory proteins.
In summary, protein degradation is a crucial cellular process involving lysosomal and non-lysosomal pathways to remove damaged, misfolded, or unnecessary proteins, thereby maintaining cellular homeostasis.
