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Protein degradation isn't just cellular housekeeping—it's a tightly regulated system that controls nearly every aspect of cell biology. When you're tested on proteomics, you need to understand that cells don't simply make proteins and let them accumulate forever. Instead, selective protein turnover drives the cell cycle, triggers apoptosis, responds to stress, and maintains the delicate balance we call proteostasis. Diseases from cancer to neurodegeneration often stem from degradation pathways gone wrong, making this content highly testable.
Don't just memorize pathway names—know why each pathway exists and what cellular problem it solves. Ask yourself: Is this pathway targeting damaged proteins? Regulating signaling? Responding to stress? Understanding the underlying logic will help you tackle comparison questions and FRQs that ask you to explain how cells maintain protein homeostasis under different conditions.
The ubiquitin system is the cell's primary "tag and destroy" mechanism. Ubiquitin, a small 76-amino acid protein, gets covalently attached to target proteins through an enzymatic cascade (E1, E2, E3 enzymes), marking them for destruction by the proteasome.
Compare: UPS vs. N-end Rule Pathway—both rely on ubiquitination and proteasomal degradation, but UPS responds to diverse signals (phosphorylation, oxidation) while the N-end rule specifically reads the N-terminal amino acid as a degradation code. If asked about how cells regulate protein stability based on intrinsic protein features, the N-end rule is your example.
When cells need to degrade large structures—entire organelles, protein aggregates, or bulk cytoplasm—they turn to the lysosome. These acidic compartments (pH ~4.5-5) contain hydrolases that break down proteins, lipids, and carbohydrates delivered through various autophagy mechanisms.
Compare: Macroautophagy vs. CMA—both deliver cargo to lysosomes, but macroautophagy engulfs bulk cytoplasm non-selectively (or selectively via adaptor proteins), while CMA targets individual proteins containing specific sequence motifs. For FRQs about selective vs. bulk degradation, this distinction is critical.
Cells constantly monitor protein folding status and compartment integrity. These surveillance systems ensure that misfolded or damaged proteins are recognized and eliminated before they can aggregate or cause toxicity.
Compare: ERAD vs. Mitochondrial Degradation—both are organelle-specific quality control systems, but ERAD exports substrates to the cytosolic proteasome while mitochondria maintain their own internal proteases. This compartmentalization reflects the bacterial ancestry of mitochondria.
Some degradation pathways don't just maintain homeostasis—they execute irreversible cellular decisions. These proteases cleave specific substrates to trigger signaling cascades, cell death, or tissue remodeling.
Compare: Caspases vs. Calpains—both are cysteine proteases that perform limited proteolysis, but caspases are activated by apoptotic signals and commit cells to death, while calpains respond to calcium signals and typically modulate protein function without killing the cell. Know which pathway to cite when asked about apoptosis (caspases) vs. signal-dependent protein modification (calpains).
| Concept | Best Examples |
|---|---|
| Ubiquitin-dependent proteasomal degradation | UPS, N-end Rule, ERAD |
| Lysosomal degradation | Macroautophagy, CMA |
| Organelle quality control | ERAD (ER), Mitochondrial proteases, Mitophagy |
| Chaperone-assisted degradation | Hsp70/CHIP pathway, CMA |
| Apoptotic proteolysis | Caspases |
| Signal-dependent proteolysis | Calpains (calcium), Caspases (death signals) |
| Stress-responsive pathways | Autophagy, HSP-mediated, UPS |
| Ubiquitin-like modifier systems | SUMOylation-dependent degradation |
Which two degradation pathways both deliver substrates to lysosomes, and what distinguishes the selectivity of each mechanism?
A cell accumulates misfolded proteins in the ER lumen. Which pathway handles this, and what happens if this pathway fails?
Compare caspase-mediated and calpain-mediated proteolysis: what activates each, and what cellular outcomes do they typically produce?
You observe increased LC3-II levels and decreased LAMP-2A expression in stressed cells. What does this suggest about which autophagy pathway(s) are active?
An FRQ asks you to explain how cells maintain proteostasis during heat stress. Which pathways would you discuss, and what role does each play in preventing protein aggregation?