Proteasome (26S, β5 subunit) !

The proteasome is the cell's shredder for proteins tagged with ubiquitin. Myeloma drugs such as bortezomib block its cutting site.

Updated 2026-11-01

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Key facts

The 20S core is a stack of four rings of seven subunits (α7β7β7α7); the active sites face the inside of the chamber, so only unfolded proteins reach them.
Three β subunits cut: β1 (caspase-like, after acidic residues), β2 (trypsin-like, after basic residues) and β5 (chymotrypsin-like, after hydrophobic residues).
Each active site uses the N-terminal threonine of the β subunit as its nucleophile (a threonine protease).
19S regulatory caps bind polyubiquitin, remove it, unfold the substrate with ATPases and open the α-ring gate.
Bortezomib, a boronic acid dipeptide, binds the β5 threonine reversibly and blocks chymotrypsin-like activity.

5LF3: the human 20S proteasome with bortezomib bound in the β5 sites (chain K shown, with the inhibitor in its active site).
The boron atom of bortezomib bonds to the hydroxyl of the N-terminal threonine (Thr1) of β5.

Gating by the 19S cap (ATP-dependent) and by other activators such as PA28.
Interferon-γ induces immunoproteasome subunits (β1i, β2i, β5i) that make better peptides for MHC class I.

Proteasome inhibitors are a backbone of multiple myeloma treatment and are also used in mantle cell lymphoma and AL amyloidosis.
Bortezomib often causes peripheral neuropathy; herpes zoster reactivation is also more frequent.

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

Which proteasome subunit does bortezomib mainly inhibit?

The β5 subunit, which has chymotrypsin-like activity.

Which amino acid is the catalytic nucleophile of proteasome active sites?

The N-terminal threonine of the active β subunits.

Why do myeloma cells depend so much on the proteasome?

They make large amounts of immunoglobulin; blocking the proteasome lets misfolded protein build up, triggering ER stress and apoptosis.

Why can folded proteins not be cut by the 20S core on its own?

The active sites are inside the closed chamber; the 19S cap must unfold the protein and open the gate.

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

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Representative model, for educational purposes only.