Map · Cell biology · Ubiquitin–proteasome

Ubiquitin–proteasome tag · cut · recycle

The cell's protein-destruction line. A tag (ubiquitin) is attached by an E1, the tagged protein is chopped in the proteasome, and deubiquitinases strip the tag back off. Layer 2 of three — pick a machine. Real crystal coordinates (RCSB PDB).

The four machines

E1 · ACTIVATE

UBA1 (ubiquitin-activating enzyme)

Ub + ATP → E1~Ub + AMP + PPᵢ

First step of tagging: forms a high-energy thioester between ubiquitin and the enzyme, spending ATP. Sets up the tag for transfer downstream.

EC 6.2.1.45 · PDB 6DC6

▶ OPEN SIMULATOR
→
E1~Ub
PROTEASOME · CHOP

PSMB5 (β5 catalytic subunit)

hydrophobic-Xaa cleaved at one site

The main protease of the proteasome: its Thr1 nucleophile cuts after bulky hydrophobic residues inside the barrel. Thr-based, not Ser or Cys.

EC 3.4.25.1 · PDB 5LE5

▶ OPEN SIMULATOR
→
peptides
DUB · STRIP (Cys)

USP7 (herpesvirus-associated DUB)

Ubiquitin released from a Ub-Xaa isopeptide

Cysteine deubiquitinase that removes the tag from a target protein. Its Cys attacks the isopeptide bond and releases free ubiquitin.

EC 3.1.2.15 · PDB 1NBF

▶ OPEN SIMULATOR
→
Ub
DUB · STRIP (Zn)

PSMD14 (RPN11, JAMM protease)

Ubiquitin released by a JAMM Zn protease

Sits on the proteasome lid and strips ubiquitin before the substrate is chopped. A zinc metalloprotease — same job as USP7, different chemistry.

EC 3.4.19.12 · PDB 8USB

▶ OPEN SIMULATOR
⤷ Tag, cut, recycle: UBA1 activates the tag, PSMB5 destroys the target, and two deubiquitinases — one Cys, one Zn — return the ubiquitin.