E1E2Mechanismen

E1E2Mechanismen describe the biochemical processes by which ubiquitin and related modifiers are activated, transferred through E1 and E2 enzymes, and conjugated to substrate proteins. This cascade is central to the ubiquitin-proteasome system and to broader regulatory pathways in eukaryotic cells.

The process begins with the E1 enzyme, which activates ubiquitin in an ATP-dependent step. Ubiquitin is adenylated to form a ubiquitin-adenylate intermediate, followed by the formation of a thioester bond between ubiquitin and a catalytic cysteine in E1. The activated ubiquitin is then transferred to a catalytic cysteine on an E2 enzyme via trans-thioesterification, producing an E2–ubiquitin conjugate (E2~Ub). E2s define certain preferences for E3 ligases and substrates, contributing to specificity and efficiency in the cascade.

E3 ligases confer substrate specificity and mediate the final transfer step. In RING-type E3s, the E2–ubiquitin complex facilitates direct transfer of ubiquitin to the substrate. In HECT-type E3s, ubiquitin is first transferred from E2 to a catalytic cysteine on the E3, and then to the substrate. A subset of E3s (RBR) combines features of both mechanisms. The diversity of E3 ligases expands the range of target proteins and regulatory contexts.

Polyubiquitin chains can be formed with different linkages, such as those through Lys48 or Lys63, yielding distinct cellular outcomes: Lys48-linked chains commonly signal proteasomal degradation, while Lys63-linked chains often participate in signaling and DNA repair. Mono-ubiquitination and chain topology further modulate outcomes.

Ubiquitin-like modifiers (for example SUMO or NEDD8) utilize related E1/E2/E3 cascades, illustrating the broad relevance of E1E2 mechanisms across cellular regulation. Dysfunctions in these pathways are linked to diseases, making components of the cascade potential targets for therapeutic intervention.