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Biochemistry · Topic

Ubiquitin–proteasome system !

Cells mark unwanted proteins with chains of a small protein, ubiquitin. The proteasome, a barrel-shaped machine, recognises the mark and chops them up.

Updated 2026-11-01

Key facts

  • Ubiquitin is a 76-amino-acid protein attached by its C-terminal glycine to lysines of the target protein.
  • Three enzymes: E1 activates ubiquitin (uses ATP), E2 carries it, E3 ligase chooses the target and transfers ubiquitin; there are hundreds of E3s, which gives specificity.
  • A chain of at least four ubiquitins linked through lysine 48 sends a protein to the 26S proteasome; lysine 63 chains and single ubiquitins signal repair, trafficking and signalling instead.
  • The 26S proteasome = a 20S core (four rings α7β7β7α7, with protease sites in β1, β2 and β5) + 19S caps that remove ubiquitin and unfold the protein using ATP.
  • Lysosomes (autophagy) degrade long-lived proteins and organelles; the proteasome degrades short-lived, regulatory and misfolded proteins.

In detail

  • 1. E1 forms a high-energy thioester with ubiquitin using ATP; ubiquitin passes to a cysteine of E2.
  • 2. E3 binds both E2 and the target (recognising degrons such as phosphorylated motifs or N-terminal residues) and catalyses transfer to a lysine.
  • 3. Repeated rounds build the polyubiquitin chain; deubiquitinating enzymes can remove it (editing and recycling).
  • 4. The 19S cap binds the chain, removes ubiquitin for reuse, unfolds the protein and threads it into the 20S chamber, where threonine proteases cut it into short peptides.
  • 5. Regulated targets include cyclins (cell cycle), p53 (via MDM2), IκB (NF-κB activation), β-catenin and misfolded ER proteins (ERAD).
  • 6. Peptides from the proteasome are loaded on MHC class I molecules and shown to cytotoxic T cells (the immunoproteasome specialises in this).
Also called
Protein degradation, Ubiquitination, E1, E2 and E3 enzymes

Clinical notes

  • Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) treat multiple myeloma: plasma cells make huge amounts of protein and die when misfolded proteins pile up.
  • High-risk HPV E6 protein recruits an E3 ligase to destroy p53, one step in cervical cancer.
  • Mutations in parkin (an E3 ligase) cause early-onset familial Parkinson disease; immunomodulatory drugs (thalidomide analogues) act by redirecting the E3 ligase cereblon.

Test yourself

Think of the answer, then tap the question to see it.

Which ubiquitin chain linkage targets a protein to the proteasome?

A chain of at least four ubiquitins linked through lysine 48.

Which enzyme of the ubiquitin cascade gives specificity for the target protein?

The E3 ubiquitin ligase; there are hundreds of them, each recognising particular substrates.

How do proteasome inhibitors work in multiple myeloma?

They block the β5 (chymotrypsin-like) site of the 20S core; myeloma cells accumulate misfolded immunoglobulin and undergo apoptosis.

How does high-risk HPV inactivate p53?

Its E6 protein recruits the E3 ligase E6AP, which ubiquitinates p53 and sends it to the proteasome.

Which proteins are degraded mainly by lysosomes rather than proteasomes?

Long-lived proteins, extracellular proteins taken up by endocytosis and whole organelles (autophagy).

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: PDB-101: Molecule of the Month: Ubiquitin (RCSB Protein Data Bank (PDB-101), 2026); PDB-101: Molecule of the Month: Proteasome (RCSB Protein Data Bank (PDB-101), 2026); UBC: Polyubiquitin-C (human) (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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