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[Biochemistry](https://durgical.com/en/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.

## Related conditions

- [Multiple myeloma](https://durgical.com/en/conditions/multiple-myeloma/)
- [Parkinson disease](https://durgical.com/en/conditions/parkinson-disease/)
- [Cervical cancer](https://durgical.com/en/conditions/cervical-cancer/)
- [Human papillomavirus (HPV) infection](https://durgical.com/en/conditions/human-papillomavirus-infection/)
- [Alzheimer disease](https://durgical.com/en/conditions/alzheimer-disease/)

## Related

- [Proteasome (26S, β5 subunit)](https://durgical.com/en/biochemistry/enzymes/proteasome/)
- [Molecular chaperones and heat shock proteins](https://durgical.com/en/biochemistry/topics/molecular-chaperones-and-heat-shock-proteins/)
- [Protein structure and folding](https://durgical.com/en/biochemistry/topics/protein-structure-and-folding/)
- [Oncogenes and tumour suppressor genes](https://durgical.com/en/biochemistry/topics/oncogenes-and-tumour-suppressor-genes/)
- [Cell organelles and their metabolism](https://durgical.com/en/biochemistry/topics/cell-organelles-and-their-metabolism/)
- [Protein targeting and signal sequences](https://durgical.com/en/biochemistry/topics/protein-targeting-and-signal-sequences/)

## 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](https://pdb101.rcsb.org/motm/60) (RCSB Protein Data Bank (PDB-101), 2026); [PDB-101: Molecule of the Month: Proteasome](https://pdb101.rcsb.org/motm/166) (RCSB Protein Data Bank (PDB-101), 2026); [UBC: Polyubiquitin-C (human)](https://www.uniprot.org/uniprotkb/P0CG48/entry) (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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