The 26S proteasome functions as a recycling machine within eukaryotic cells. This large, multi-protein complex breaks down unneeded, damaged, or misfolded proteins into smaller components. Its activity maintains the internal cellular balance, ensuring proper function and survival. Without this system, cells would accumulate harmful protein aggregates, leading to dysfunction and cell death.
Components of the 26S Proteasome
The 26S proteasome is composed of two sections: the 20S core particle and one or two 19S regulatory particles. The 20S core particle forms a barrel-shaped structure, often likened to a shredder, housing the proteolytic active sites. This core is made of four stacked rings: two outer alpha rings and two inner beta rings. The beta rings contain the protein-cutting enzymes that break down proteins into smaller peptides.
Attached to one or both ends of the 20S core are the 19S regulatory particles, which act like “lids” or “gatekeepers.” Each 19S particle divides into a “base” and a “lid” subcomplex. The base associates with the 20S core and contains a ring of six AAA-ATPase proteins that provide energy for the proteasome’s function. The lid subcomplex, positioned above the base, recognizes target proteins and removes their ubiquitin tags.
The Protein Recycling Process
Protein degradation by the 26S proteasome begins with a tagging system involving ubiquitin. Proteins destined for destruction are marked with a chain of ubiquitin molecules. This ubiquitination is carried out by a series of enzymes: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases. The ligases provide specificity, recognizing the target protein and attaching the ubiquitin tag.
Once tagged, the ubiquitinated protein is recognized by receptors on the 19S regulatory particle. Before the protein enters the 20S core, deubiquitinating enzymes (DUBs) remove the ubiquitin tags, which are recycled. This ensures ubiquitin is not degraded along with the target protein.
Following deubiquitination, AAA-ATPase proteins within the 19S regulatory particle use energy from ATP hydrolysis to unfold the targeted protein. This converts chemical energy from ATP into the force needed to linearize the protein structure. The unfolded polypeptide chain then threads into the central chamber of the 20S core particle. Inside, proteolytic active sites on the beta subunits cleave the protein into short peptides. These peptides are released from the proteasome and can be further broken down into individual amino acids by other cellular enzymes, making them available for new protein synthesis.
Central Role in Cellular Health
The 26S proteasome’s activity maintains proteome homeostasis, the balance between protein synthesis and degradation within a cell. This balance supports cellular adaptation and survival. By selectively degrading proteins, the proteasome prevents the accumulation of misfolded or damaged proteins that could aggregate and disrupt cellular functions.
Beyond waste disposal, the proteasome regulates numerous cellular processes. It controls the cell cycle by degrading proteins like cyclins, allowing cells to progress through different growth phases. Its involvement extends to DNA replication and repair, where it helps remove proteins that might impede these processes or degrade damaged components. The proteasome also participates in gene expression by regulating the stability of transcription factors, influencing which genes are turned on or off.
It also plays a role in immune responses by generating peptides from degraded proteins. These are then presented on the cell surface to alert the immune system to potential threats. This broad regulatory capacity ensures cells can respond effectively to internal and external cues, adapt to stress, and maintain their integrity.
Proteasome and Medical Breakthroughs
Understanding the 26S proteasome’s function has led to advancements in medicine, particularly in cancer treatment. Dysregulation of the proteasome can contribute to various diseases, including neurodegenerative disorders and cancer. In many cancers, the proteasome’s activity is abnormally high, allowing cancer cells to rapidly degrade tumor suppressor proteins and evade programmed cell death, leading to uncontrolled proliferation.
This insight paved the way for proteasome inhibitors, a class of drugs designed to block the proteasome’s activity. By inhibiting the proteasome, these drugs cause an accumulation of unwanted proteins within cancer cells, triggering stress responses and ultimately leading to cell death. Bortezomib, the first proteasome inhibitor approved for clinical use, transformed the treatment of multiple myeloma, a type of blood cancer. Other inhibitors have also been developed and are used to treat multiple myeloma and mantle cell lymphoma. These therapeutic agents highlight the proteasome as a promising target for future drug development against diseases where protein degradation pathways are compromised.