Degrons are specific sequences or structural motifs within proteins that signal their degradation. These internal “tags” mark proteins for removal, maintaining cellular balance and function. They can be short amino acid sequences or specific exposed amino acids, and a single protein can contain multiple degrons. Degrons are found in diverse organisms, from yeast to humans, and are recognized by cellular machinery involved in protein turnover.
Understanding Cellular Protein Recycling
Cells constantly recycle proteins to maintain health and respond to changing conditions. The primary pathway for this regulated protein breakdown in eukaryotes is the ubiquitin-proteasome system (UPS). This system acts like a cellular recycling plant, dismantling unwanted or damaged proteins.
The UPS involves ubiquitin, a small protein that acts as a “tag” for destruction. Ubiquitin is activated and then attached to target proteins by E3 ubiquitin ligases. This attachment, called ubiquitination, often involves linking multiple ubiquitin molecules together, forming a chain that signals the protein for degradation.
Degrons are where this tagging system initiates. They are the specific signals within a protein that E3 ubiquitin ligases recognize, leading to the attachment of ubiquitin tags. Once tagged, the ubiquitinated protein is recognized by the 26S proteasome, a large protein complex that unfolds and breaks down the protein into smaller peptides. The ubiquitin molecules are then released and recycled for future use.
How Degrons Control Cell Processes
Degrons play diverse roles in cellular functions by controlling protein levels. Their ability to signal for degradation at specific times or in response to particular cues makes them key regulators of cell behavior. Different types of degrons exist, such as those recognized based on their N-terminal amino acid (N-degrons), internal sequences, or post-translational modifications like phosphorylation.
One significant role is in cell cycle regulation, where degrons ensure cell division proceeds in an orderly manner. Proteins that promote cell division are often degraded at specific moments to allow progression through different phases, while others are removed to halt the cycle if issues arise. For example, the Anaphase-Promoting Complex/Cyclosome (APC/C) and SCF complexes recognize distinct degrons to regulate proteins at different cell cycle stages, such as mitosis or G1-S progression.
Degrons are also involved in the cellular stress response, helping cells adapt to challenging environments. When proteins become damaged or misfolded due to stress, degrons can mark them for removal, preventing their accumulation and maintaining cellular proteostasis. For instance, certain N-degrons can sense fluctuating oxygen levels and reactive oxygen species, triggering protein degradation to cope with stress.
Degrons also guide development and differentiation by ensuring proteins are present only when needed. The removal of specific proteins at certain developmental stages, facilitated by degrons, allows for the proper formation of tissues and organs. Different “reader” proteins or E3 ligases recognize these varied degrons, providing the specificity required for diverse regulatory functions.
Degrons in Disease and Medicine
Dysfunctional degrons can contribute to the development and progression of various diseases. If a degron is mutated and a protein becomes too stable, it might persist in the cell when it should be degraded, leading to uncontrolled cell growth or the accumulation of harmful proteins. For instance, mutations that impair degron function in oncogenic proteins, such as MYC or NRF2, can lead to their prolonged presence, promoting cancer. Similarly, issues with protein clearance pathways, which involve degrons, are linked to neurodegenerative diseases where misfolded proteins accumulate and damage cells.
Scientists are leveraging the understanding of degrons to develop new medical treatments, particularly through targeted protein degradation (TPD). This approach aims to remove disease-causing proteins rather than just inhibiting their activity. One prominent TPD strategy involves Proteolysis-Targeting Chimeras, or PROTACs.
PROTACs are designed as “molecular glues” that bring a target protein into close proximity with an E3 ubiquitin ligase, an enzyme responsible for adding ubiquitin tags. This artificial proximity forces the E3 ligase to ubiquitinate the target protein, even if it doesn’t have a natural degron the ligase would normally recognize. Once ubiquitinated, the target protein is degraded by the proteasome. This “event-driven” mechanism means PROTACs can be recycled and used repeatedly, potentially allowing for lower drug doses and the ability to target proteins previously considered “undruggable” because they lack easily accessible binding pockets for traditional inhibitors.