Ubiquitin-Proteasome Cascade

Ligation Cascade

E3 ligase rate (ubiquitination) 1.0×

DUB proofreading rate 0.4×

K48 chain threshold (min length) 4

ATP / unfoldase speed 1.0×

Live Readouts

Free ubiquitin pool

Substrates in cytosol

In proteasome

Degraded / min

0.0

Substrate protein

Ubiquitin monomer (chain)

26S proteasome (19S cap + 20S core)

Peptide fragments (released)

How it works

Protein degradation via the ubiquitin-proteasome system is a three-enzyme relay followed by ATP-driven unfolding:

E1 + Ub + ATP → E1~Ub (activated, AMP + PPi released)
E1~Ub + E2 → E2~Ub
E2~Ub + E3 + substrate-Lys → substrate-Ub(n) + E2
repeat → K48-linked poly-Ub chain grows on substrate

Chain length L follows a birth-death balance between ligation and deubiquitinase (DUB) removal:

dL/dt = k_lig · [E3 active] − k_dub · L
capture when L ≥ threshold (this sim: 2–8, canonical K48 minimum ≈ 4)

Once a substrate crosses the threshold, the 19S regulatory particle's ring of six AAA+ ATPases grips an exposed unstructured tail and threads the chain through its central pore, unfolding the protein processively — one ~2 residue "step" per ATP hydrolysed — into the 20S core's proteolytic chamber, where it is cleaved into short peptides. Ubiquitin itself is recycled by proteasome-associated DUBs before the substrate enters the pore, so the ubiquitin pool never leaves the system.

E3 ligase rate — how fast poly-Ub chains grow on each tagged substrate.
DUB rate — competing chain-trimming; too high and substrates never reach threshold (a real proofreading checkpoint against premature degradation).
K48 threshold — minimum chain length the proteasome's Rpn10/Rpn13 ubiquitin receptors need to commit a substrate to degradation.
ATP / unfoldase speed — throughput of the two proteasomes shown; each processes one substrate at a time.

Real-world relevance: this pathway degrades >80% of cellular proteins, drives cell-cycle checkpoints (cyclin destruction), clears misfolded proteins, and is the direct target of proteasome-inhibitor cancer drugs (bortezomib) and PROTAC-style targeted-degradation therapeutics.

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