Ubiquitin proteasome pathway.pptx

Protein degradation- Ubiquitin proteasome pathway

1. P:1 U:2 Vedanti Gharat M.Sc. Part -1 Roll No. - 09 UBIQUITIN- PROTEASOME PATHWAY

2. PROTEIN DEGRADATION The levels of proteins within cells are determined not only by rates of synthesis but also by rates of degradation. The half-lives of proteins within cells vary widely and differential rates of protein degradation are an important aspect of cell regulation . Many rapidly degraded proteins function as regulatory molecules. In eukaryotic cells, the ubiquitin-proteasome pathway is the major mediator of regulated protein degradation.

3. UBIQUITIN- PROTEASOME PATHWAY Ubiquitin is a 76- A.A polypeptide that is highly conserved in all eukaryotes. Proteins are marked for degradation by the attachment of ubiquitin to the amino group of the side chain of a lysine residue. The selective addition of ubiquitin to target proteins is a multistep process.

4. First, ubiquitin is activated by being attached to a ubiquitin-activating enzyme, E1. The ubiquitin is then transferred to a second enzyme, called ubiquitin conjugating enzyme (E2). The ubiquitin is then transferred to the target protein by E2 complexed with a third protein, called ubiquitin ligase or E3. E3s mediate the selective recognition of target proteins by binding to both a substrate and an E2 . (Mammalian cells contain only 2 ubiquitin E1s, but have 40 E2s and about 600 E3s .)

5. Figure. The ubiquitin-proteasome pathway Ubiquitin is first activated by the enzyme E1. Activated ubiquitin is then transferred to one of several different ubiquitin- conjugating enzymes (E2). A ubiquitin ligase (E3) then associates with both E2 and a substrate protein to direct the transfer of ubiquitin to a specific target. Proteins are marked for rapid degradation by the covalent attachment of multiple molecules of ubiquitin to form a polyubiquitin chain. The polyubiquitinated proteins are degraded by a protease complex (the proteasome).

6. Proteins targeted for degradation are marked by the addition of multiple ubiquitins to form a polyubiquitin chain, which is catalyzed by some E3s. Such polyubiquinated proteins are recognized and degraded by a large, multi subunit protease complex, called the proteasome . Ubiquitin is released in the process, so it can be reused in another cycle.

7. An interesting example of controlled degradation is provided by proteins (known as cyclins ), that regulate progression through the division cycle of eukaryotic cells. 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 Cdk1 . The association of cyclin B with Cdk1 is required for activation of the Cdk1 kinase, which initiates the events of mitosis by phosphorylating various cellular proteins .

8. Figure. Cyclin degradation during the cell cycle. The progression of eukaryotic cells through the division cycle is controlled in part by the synthesis and degradation of cyclin B , which is a regulatory subunit of the Cdk1 protein kinase. Synthesis of cyclin B during interphase leads to the formation of an active cyclin B–Cdk1 complex, which induces entry into mitosis. Rapid degradation of cyclin B by the proteasome then leads to inactivation of the Cdk1 kinase, allowing the cell to exit mitosis and return to interphase of the next cell cycle.

9. Cdk1 also activates a ubiquitin ligase that targets cyclin B for degradation toward the end of mitosis. This degradation of cyclin B inactivates Cdk1, allowing the cell to exit mitosis and progress to interphase of the next cell cycle. The ubiquitylation of cyclin B is a highly selective reaction, targeted by a nine amino-acid cyclin B sequence called the destruction box . 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.

10. BIBLIOGRAPHY The cell- molecular approach by G. Cooper. thankyou