Targeted Protein Degradation
Why are proteins degraded?
In order to keep a cell working it needs to remove:
incorrectly synthesized proteins (with errors in amino acid
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
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
Lysosomes can also target damaged organelles in a process
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
Ubiquitin (a small 76-residue protein) is attached to the
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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