The ubiquitin-proteasome system handles individual soluble misfolded proteins. A cascade of three enzyme classes — E1 activating enzyme, E2 conjugating enzyme, and E3 ubiquitin ligase — attaches ubiquitin to a lysine on the substrate. The E3 ligase determines substrate specificity, which is why the human genome encodes hundreds of them. Repeated rounds of conjugation build a polyubiquitin chain, and a chain of at least four ubiquitin units linked through lysine 48 is recognized by the 26S proteasome. The proteasome is a barrel-shaped protease complex: the 19S regulatory particle recognizes the chain, unfolds the substrate, and feeds it into the 20S core, where processive proteolysis generates short peptides. The entire process consumes ATP, both for ubiquitin conjugation and for substrate unfolding. A misfolded protein that cannot be refolded is therefore not simply discarded; it is actively selected, tagged, unfolded, and degraded.
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Proteostasis: Folding, Chaperones, and Degradation
Tagging a misfolded protein for destruction
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Follow the chain of events from left to right. The E1 enzyme activates ubiquitin in an ATP-dependent step and hands it to an E2 conjugating enzyme. The E3 ligase is the matchmaker: it binds a specific misfolded substrate and positions the E2 so that ubiquitin is transferred to a lysine on the client. Repeat that cycle and you build a polyubiquitin chain. A chain of at least four ubiquitins linked through lysine 48 is the signal that the 26S proteasome recognizes. The 19S cap binds the chain, uses ATP to unfold the substrate, and threads it into the 20S core, where it is cut into short peptides. Notice two things. First, the E3 determines which proteins get destroyed, which is why there are hundreds of E3 ligases. Second, the whole process costs ATP, so degradation is not free — it competes with folding for the same energy budget.
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