The proteasome is a complex molecular machine found within eukaryotic cells, serving as the cell’s primary “recycling plant” for proteins. It is responsible for degrading unwanted or damaged proteins into smaller peptides, a process known as proteolysis. This function is fundamental for various cellular processes, helping to clear cellular “waste” and maintain health.
The 20S Core Particle
The 20S core particle forms the catalytic heart of the proteasome, resembling a hollow cylinder. This structure is composed of four stacked rings, each containing seven proteins, totaling 28 subunits. The two outer rings are made of alpha (α) subunits, which primarily serve as structural scaffolds and regulate the entry of substrates into the central chamber.
The two inner rings consist of beta (β) subunits, where the actual protein cleavage takes place. Three of the seven beta subunits in eukaryotic proteasomes contain the catalytic sites responsible for breaking down proteins. These active sites are located on the inner surface of the beta rings, within the central chamber of the complex. This design ensures that protein degradation is compartmentalized and controlled.
The 19S Regulatory Particle
The 19S regulatory particle, also known as the 19S cap, attaches to one or both ends of the 20S core particle, forming the larger 26S proteasome. This regulatory cap acts as a gatekeeper and preparer of proteins for degradation. It is composed of approximately 19 subunits, organized into two main sub-complexes: the base and the lid.
The base sub-complex directly binds to the alpha ring of the 20S core and contains six ATPase subunits. These ATPases are responsible for the energy-dependent unfolding and translocation of proteins into the 20S core. The base also includes ubiquitin-binding sites, which recognize proteins tagged for degradation. The lid sub-complex consists of at least nine non-ATPase subunits, including the deubiquitinating enzyme Rpn11, which helps remove ubiquitin tags from proteins before they are degraded.
Structural Basis of Proteasome Function
The distinct structures of the 20S and 19S particles work in concert to achieve selective protein degradation. The process begins with the recognition of proteins marked for destruction, typically by the attachment of a small protein called ubiquitin, forming a polyubiquitin chain. The 19S regulatory particle, through its ubiquitin-binding sites, recognizes these ubiquitinated proteins.
Following recognition, the ATP-dependent ATPase subunits within the 19S base engage the target protein. These ATPases use energy from ATP hydrolysis to unfold the protein, converting its complex three-dimensional structure into a linear polypeptide chain. This unfolding is a prerequisite for the protein to enter the narrow central chamber of the 20S core particle.
The unfolded protein is then translocated into the 20S core through its narrow opening. Once inside the central chamber, the protein encounters the catalytic sites located in the beta rings of the 20S core. Here, the protein is rapidly cleaved into smaller peptides, typically 3 to 25 amino acids in length.
Why Proteasome Integrity Matters
An intact proteasome is important for maintaining cellular health. It plays a central role in protein homeostasis, also known as proteostasis, by actively removing misfolded, damaged, or unneeded proteins. This prevents the accumulation of potentially toxic protein aggregates that can disrupt cellular processes.
The proteasome also regulates various cellular activities, including cell cycle progression, gene expression, and immune responses. For instance, by degrading specific proteins that control cell division, the proteasome helps prevent the uncontrolled proliferation of cells. Dysfunction of the proteasome can lead to an imbalance in protein levels, increased cellular stress, and the buildup of abnormal proteins. Its continuous and precise operation is necessary for the proper functioning of eukaryotic cells.