![]() Lysosomes are membrane-enclosed organelles that contain an array of digestive enzymes, including several proteases (see Chapter 9). The other major pathway of protein degradation in eukaryotic cells involves the uptake of proteins by lysosomes. Mutations of this sequence prevent cyclin B proteolysis and lead to the arrest of dividing cells in mitosis, demonstrating the importance of regulated protein degradation in controlling the fundamental process of cell division. The ubiquitination of cyclin B is a highly selective reaction, targeted by a 9-amino-acid cyclin B sequence called the destruction box. This degradation of cyclin B inactivates Cdc2, allowing the cell to exit mitosis and progress to interphase of the next cell cycle. Cdc2 also activates a ubiquitin-mediated proteolysis system that degrades cyclin B toward the end of mitosis. The association of cyclin B with Cdc2 is required for activation of the Cdc2 kinase, which initiates the events of mitosis (including chromosome condensation and nuclear envelope breakdown) by phosphorylating various cellular proteins. The entry of all eukaryotic cells into mitosis is controlled in part by cyclin B, which is a regulatory subunit of a protein kinase called Cdc2 (see Chapter 14). ![]() An interesting example of such controlled degradation is provided by proteins (known as cyclins) that regulate progression through the division cycle of eukaryotic cells ( Figure 7.40). Different members of the E2 and E3 families recognize different substrate proteins, and the specificity of these enzymes is what selectively targets cellular proteins for degradation by the ubiquitin- proteasome pathway.Ī number of proteins that control fundamental cellular processes, such as gene expression and cell proliferation, are targets for regulated ubiquitination and proteolysis. Most cells contain a single E1, but have many E2s and multiple families of E3 enzymes. In other cases, the ubiquitin may be transferred directly from E2 to the target protein in a complex with E3. In some cases, the ubiquitin is first transferred from E2 to E3 and then to the target protein (see Figure 7.39). The final transfer of ubiquitin to the target protein is then mediated by a third enzyme, called ubiquitin ligase or E3, which is responsible for the selective recognition of appropriate substrate proteins. The ubiquitin is then transferred to a second enzyme, called ubiquitin-conjugating enzyme (E2). First, ubiquitin is activated by being attached to the ubiquitin-activating enzyme, E1. Since the attachment of ubiquitin marks proteins for rapid degradation, the stability of many proteins is determined by whether they become ubiquitinated. ![]() Activated ubiquitin is then transferred to one of several different (more.) Ubiquitin is first activated by the enzyme E1. Proteins are marked for rapid degradation by the covalent attachment of several molecules of ubiquitin. ![]()
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