Protein Degradation
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- Removes misfolded proteins
- Regulates the amount of a protein in the cell at a time
Two major pathways
1) Ubiquitin-dependent pathway
2) Autophagy (targets old and worn-out organelles)
Proteolysis
Break down of proteins into smaller peptides or amino acids
Clinical Correlation
- Pathologic accumulation of misfolded proteins results in various diseases such as sickle cell anemia and certain neurodegenerative illnesses (Huntington's disease, Alzheimer's disease, and Creutzfeldt-Jacob disease)
- "Central cylinder"
- Comprised of four rings – two inner rings (seven beta subunits each) and two outer rings (seven alpha subunits each)
- Has protease activity
- "Cap" subunit
- ATPas sites – provide energy for protein degradation and unfolding by using ATP
- Ubiquitin binding sites – recognize proteins tagged for degradation
Protein tagging with ubiquitin
1) Ubiquitin added to cysteine side chain of the E1 protein (ubiquitin-activating enzyme)
2) E1 protein becomes bound to E2 (ubiquitin conjugating enzyme) and E3 protein complex (ubiquitin ligase)
3) Ubiquitin transferred to cysteine side chain on the E2 protein
4) Misfolded protein becomes bound to E3 protein
5) Ubiquitin transferred to lysine side chain on the misfolded protein
6) Repeat steps 1-5 to polyubiquitinate the misfolded protein – polyubiquitin chain is the signal for protein degradation in the proteasome
Proteasomal degradation of the tagged protein
1) Misfolded protein with polyubiquitin chain is recognized by 19S cap of the proteasome
2) Using ATP as an energy source, protein is unfolded, ubiquitin is released, and the protein is translocated into the 20S subunit to be degraded (unknown if unfolding or removal of ubiquitin happens first, but both must occur before translocation can happen)
3) When translocated protein reaches the proteolytic sites, it is cleaved and peptide fragments are released into the cytoplasm for further degradation