The proteasome is a multi-subunit machine that unfolds and degrades proteins. How is its activity regulated such that it only degrades certain proteins?

The proteasome is a multi-subunit machine present within cells, playing a crucial role in maintaining protein homeostasis by unfolding and degrading proteins that are damaged, misfolded, or no longer needed. This process is essential for the proper functioning of the cell, as impeded protein degradation can result in cellular dysfunction and various diseases.

The proteasome's selectivity in degrading proteins relies on the Ubiquitin-Proteasome Pathway (UPP). In this well-regulated pathway, proteins are first labeled with ubiquitin, a small protein, via an enzymatic cascade involving three types of enzymes: E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase. The attachment of ubiquitin onto the target protein occurs through a covalent bond between its C-terminal glycine residue and a lysine residue of the target protein. This ubiquitin "tag" then signals the proteasome to recognize and degrade the protein.

The proteasome features an N-terminal threonine protease core, a cylinder-shaped structure with a central pore in which protein degradation occurs. Before entering the core, substrates must be recognized and accepted by a subunit on the proteasome called the regulatory particle. This particle specifically recognizes proteins tagged by ubiquitin chains and unwinds the proteins before allowing them to pass through the pore into the proteolytic chamber. Inside the proteolytic chamber, proteins are subsequently degraded into smaller peptides.

Prior to degradation, the ubiquitin tags on the target protein must be removed and recycled for future use. This is accomplished by deubiquitinating enzymes (DUBs), which cleave the ubiquitin moieties from the protein. The protein, now devoid of its ubiquitin tags, can be efficiently degraded by the proteasome, ensuring the fidelity and efficiency of the process.

In addition to the regulation provided by the ubiquitin tagging, proteasome activity can also be modulated in response to various cellular signals and conditions. For example, the production and assembly of proteasome subunits can be upregulated under conditions that cause an increased demand for protein degradation, such as during stress responses. Furthermore, many post-translational modifications (e.g., phosphorylation, acetylation, and glycosylation) can modulate proteasome function and contribute to its selectivity and activity. In conclusion, the proteasome selectively degrades proteins through a combination of substrate-specific ubiquitination, recognition of ubiquitinated proteins by the regulatory particle, and additional layers of cellular regulation. This ensures that only certain proteins are targeted for degradation, maintaining overall protein homeostasis in the cell.