Fig. 1

The ubiquitination process and ubiquitin code. a. The cascade of ubiquitin modification. Ubiquitin modification involves three successive steps catalyzed by three types of enzymes: (1) E1 ubiquitin-activating enzyme activates ubiquitin in an ATP-dependent manner; (2) the activated ubiquitin protein is transferred to E2 ubiquitin- conjugating enzyme via a transesterification reaction; (3) E3 ubiquitin ligase bridges the ubiquitin-loaded E2 and targeted protein to facilitate the binding of ubiquitin with a substrate lysine. These attached ubiquitin molecules can be cleaved by deubiquitinases from substrates. Polyubiquitin chains represented by the K48 linkage will lead to 26S proteasome‑mediated proteolysis. b. Differential catalytic domains and transfer modes of three classes of E3 ligases. c. Topological versatility in protein ubiquitination