Targeted Protein Degradation

In order to keep a cell working it needs to remove:

• incorrectly synthesized proteins (with errors in amino acid sequence)
• damaged proteins (i.e. oxidative damage)
• cell-cycle specific proteins
• other signaling proteins which are no longer necessary

One mechanism of protein degradation is via lysosomes.  Lysosomes are acidic vesicles that contain about 50 different enzymes involved in degradation:

• proteases (cathepsins):  cleave peptide bonds
• phosphatases:  remove covalently bound phosphates
• nucleases:  cleave DNA/RNA
• lipases:  cleave lipid molecules
• carbohydrate-cleaving enzymes:  remove covalently bound sugars from glycoproteins

• Lysosomes often secrete their contents into the extracellular medium via exocytosis.
• Lysosomes can also target damaged organelles in a process called autophagy.
• Sometimes, lysosomes are triggered to rupture inside a cell, resulting in autolysis, also called apoptosis or programmed cell death.

Another major mechanism is via ubiquitin labeling of surplus proteins:

• Ubiquitin (a small 76-residue protein) is attached to the protein:
• First, an activating enzyme attaches itself to the carboxy terminus of free ubiquitin in an ATP-dependent process.
• Then, the activated ubiquitin is transferred onto a second enzyme which at the same time recognizes damaged proteins.
• The activated ubiquitin is then covalently linked to lysine residues on the surface of the damaged protein.

• These ubiquitin-tagged proteins are now recognized by specific proteases in the cytosol which in turn cleave and degrade the tagged protein.

• These proteases are combined in a very large protein complex called the proteasome.

• The proteasome (20S) is comprised of 28 subunits and has a molecular weight of 700 kDa:

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