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Chapter: Biochemistry: Protein Synthesis: Translation of the Genetic Message

Protein Degradation

Protein Degradation
How does the cell know which proteins to degrade?

Protein Degradation

One of the most often overlooked controls of gene expression occurs at the level of the degradation of proteins. Proteins are in a dynamic state in which they are turned over often. Athletes are painfully aware of this because it means that they must work very hard to get in shape, but then they get out of shape very quickly. Some classes of proteins experience a 50% turnover every three days. In addition, abnormal proteins that were formed from errors in either transcription or translation are degraded quickly. It is believed that a single break in the peptide backbone of a protein is enough to trigger the rapid degradation of the pieces, because breakdown products from natural proteins are rarely seen in vivo.

How does the cell know which proteins to degrade?

If protein degradation is so quick, clearly it is a process that must be heavily controlled to avoid destruction of the wrong polypeptides. The degradation pathways are restricted to degradative subcellular organelles, such as lysosomes, or to macromolecular structures called proteasomes. Proteins are directed to lysosomes by specific signal sequences, often added in a posttranslational modification step. Once in the lysosome, the destruction is nonspecific.


Proteasomes are found in both prokaryotes and eukaryotes, and specific pathways exist to target a protein so that it complexes with a proteasome and is degraded.

In eukaryotes, the most common mechanism for targeting protein for destruction in a proteasome is by ubiquitinylation. Ubiquitin is a small polypeptide (76 amino acids) that is highly conserved in eukaryotes. There is a high  degree of homology between the sequences in species as widespread as yeast and humans. When ubiquitin is linked to a protein, it condemns that protein to destruction in a proteasome. Figure 12.23 shows the mechanism of ubiquitinylation.

Three enzymes are involved—ubiquitin-activating enzyme (E1), ubiquitin-carrier protein (E2), and ubiquitin-protein ligase (E3). The ligase transfers the ubiquitin to free amino groups on the targeted protein, either the N-terminus or lysine side chains. Proteins must have a free α-amino group to be susceptible, so proteins that are modified at the N-terminus—with an acetyl group, for instance—are  protected from ubiquitin-mediated degradation. The nature of the N-terminal amino acid also influences its susceptibility to ubiquitinylation. Proteins with Met, Ser, Ala, Thr, Val, Gly, or Cys at the N-terminus are resistant. Those with Arg, Lys, His, Phe, Tyr, Trp, Leu, Asn, Gln, Asp, or Glu at the N-terminus have very short half-lives, between 2 and 30 minutes. Proteins with an acidic residue at the N-terminus have a requirement for tRNA as part of their destruction pathway. The tRNA for arginine, Arg-tRNAarg, is used to transfer arginine to the N-terminus, making the protein much more susceptible to the ubiquitin ligase (Figure 12.24). The following Biochemical Connections box gives an interest-ing example of how transcription regulation and protein degradation work together to control the process of acclimation to high altitude.


Proteins are degraded in subcellular organelles, such as lysosomes, or in macromolecular structures called proteasomes.

Many proteins are targeted for destruction by being bound to a protein called ubiquitin.

The nature of the amino acid sequence at the N-terminus is often very important to control of the timing of destruction of a protein.

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