Overview of the Ubiquitin-Proteasome System of Protein Degradation

Proteins are targeted for degradation by the ubiquitin-proteasome system (UPS) through the covalent attachment of ubiquitin molecules to specific lysine residues on the target protein. This process involves the sequential action of three main enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase).

Here’s a summary of how proteins are targeted for degradation:

1. Ubiquitination: The process starts with the activation of ubiquitin by E1 in an ATP-dependent manner. Activated ubiquitin is then transferred to an E2 enzyme. The E2 enzyme, in conjunction with an E3 ligase, facilitates the transfer of ubiquitin from the E2 enzyme to the target protein. The E3 ligase recognizes specific target proteins and mediates the transfer of ubiquitin to lysine residues on the target protein, forming a ubiquitin chain.
2. Ubiquitin Chain Assembly: Ubiquitin itself contains seven lysine residues (K6, K11, K27, K29, K33, K48, and K63), each of which can serve as an attachment site for the formation of polyubiquitin chains. While K48-linked polyubiquitin chains are the most well-characterized signal for proteasomal degradation, other types of polyubiquitin linkages, such as K11 and K63, can also target proteins for degradation by the proteasome or other degradation pathways, depending on the context and the nature of the ubiquitin chain-binding proteins.
3. Proteasomal Degradation: Proteins marked with polyubiquitin chains are recognized and degraded by the 26S proteasome, a large multi-subunit protease complex. The polyubiquitin chain serves as a signal for recognition and subsequent unfolding of the protein substrate by the proteasome. The substrate is then translocated into the proteolytic core of the proteasome, where it is cleaved into small peptides.

Regarding the fate of peptides generated by proteasomal degradation:

• The peptides produced by proteasomal degradation are typically 7-8 amino acids in length.
• These peptides are released into the cytosol and can be further processed by cytosolic peptidases.
• The resulting peptides can serve as a source of amino acids for protein synthesis or can be presented on the cell surface by major histocompatibility complex (MHC) molecules for immune surveillance.

In summary, while K48-linked polyubiquitin chains are the most commonly associated with proteasomal degradation, other types of polyubiquitin linkages can also target proteins for degradation by the proteasome or other degradation pathways. The peptides generated by proteasomal degradation can have various fates, including serving as a source of amino acids or being presented on MHC molecules.

End of Section 3.2

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Source: ChatGPT response prompted and edited by Joel Graff.

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