The Ubiquitin-Proteasome System: An Overview
The Ubiquitin-Proteasome system (UPS) is a highly complex, temporally controlled and conserved pathway that plays a major role in a myriad on cellular functions. From cellular differentiation to cell death, the UPS has a large hand in determining the fate of cells and proteins. It is important to understand the UPS, as discrepancies within the pathway usually indicate pathogenesis of many diseases.
To understand the UPS, let us not start at the beginning, but at the end. The purpose of the UPS is to conjugate a ubiquitin molecule to a protein that is destined for degradation. Why is this so significant? Maladaptive UPS pathways, and proteins that are not adequately degraded (specifically those that are mutated, misfolded, or overexpressed), are the baseline etiologies of detrimental cellular function. The UPS pathway is a three-step process that ends with the ubiquitin conjugation to a protein. Ubiquitin tags a protein either as a single molecule via monoubiquitinatation or as an oligomerized chain via polyubiquitination. Ubiquitin has several different lysines, or linkage points, where it can tag itself to a protein to indicate degradation: M1, K6, K11, 27, K33, K48, K63. Where the ubiquitin molecule adheres specifically will determine how that protein is degraded. This can be proteasomal or lysosomal.
How does the ubiquitin molecule/molecules adhere to the destined protein? This is where the three-step, ATP-dependent process and its understanding become integral. This three-step pathway has another name which explains the milestones of each step, E1E2E3 pathway.
The initiating step, E1, is known as the activating step. An activating enzyme, such as UBE1 (Ubiquitin-activating enzyme E1), activates ubiquitin and begins a cascade of enzymatic/substrate activity. This is the alarm clock of the UPS, alerting the ubiquitin that the time to degrade is now.
The intermediate step, E2, is known as the conjugating step. A conjugating enzyme, such as UBE2D2 (Ubiquitin-conjugating enzyme E2 D2), grabs the ubiquitin molecule and creates an E2-Ubiquitin conjugate intermediate. This is the ubiquitin-baton passer of the Ubiquitin-Proteasome System, preparing to cross the threshold to pass the ubiquitin to the final step.
The final step, E3, is known as the ligase step. A ligase, such as MurRF1 (muscle-specific RING-finger protein 1), takes the ubiquitin molecule from the Ub-E2 intermediate and completes the pathway by conjugating the ubiquitin to the target substrate. This is the anchor of the UPS, handing off and finally linking the ubiquitin to the protein.
There are many different E1, E2 and E3 enzymes. Problematic enzymes in any of these areas can lead to an improperly functioning UPS. Deficit enzymes can be a cause of epigenetic or environmental factors. Studying each portion of the pathway and its individual enzymes is an active task of many therapeutic-focused labs and industries.
As our knowledge of the UPS grew, a new model of UPS drug was created. This model is known as a PROTAC ®, or a PRoteolytic TArgeting Chimera. A PROTAC recruits the UPS in order to target and degrade target proteins. The selectivity of these compounds is attractive, as many past therapeutics have poor selectivity resulting in proximity deficits and clinical side effects (akin to the chemotherapy attacking the entire system, not just the metastasizing cancer system). PROTAC is not the endgame model of designer UPS drugs – new and innovative compounds are being theorized and created to recruit the UPS to treat many drug-resistant diseases. LifeSensors looks forward to assisting and streamlining this drug discovery process with these ambitious researchers across the globe.