Ubiquitin Marks Cytosolic Proteins for Degradation in Proteasomes

In addition to chemical modifications and processing, the activity of a cellular protein depends on the amount present, which reflects the balance between its rate of synthesis and rate of degradation in the cell. The numerous ways that cells regulate protein synthesis are discussed in later chapters. In this section, we examine protein degradation, focusing on the major pathways for degrading cytosolic proteins.

The life span of intracellular proteins varies from as short as a few minutes for mitotic cyclins, which help regulate passage through mitosis, to as long as the age of an organism for proteins in the lens of the eye. Eukaryotic cells have several intracellular proteolytic pathways for degrading misfolded or denatured proteins, normal proteins whose concentration must be decreased, and extracellular proteins taken up by the cell. One major intracellular pathway is degradation by enzymes within lysosomes, membrane-limited organelles whose acidic interior is filled with hydrolytic enzymes. Lysosomal degradation is directed primarily toward extracellular proteins taken up by the cell and aged or defective organelles of the cell (see Figure 5-20).

Distinct from the lysosomal pathway are cytosolic mechanisms for degrading proteins. Chief among these mechanisms is a pathway that includes the chemical modification of a lysine side chain by the addition of ubiquitin, a 76-residue polypeptide, followed by degradation of the ubiquitin-tagged protein by a specialized proteolytic machine. Ubiquitination is a three-step process (Figure 3-13a):

■ Activation of ubiquitin-activating enzyme (E1) by the addition of a ubitiquin molecule, a reaction that requires ATP

■ Transfer of this ubiquitin molecule to a cysteine residue in ubiquitin-conjugating enzyme (E2)

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