polyubiquitineketens

Polyubiquitin chains are polymers formed by linking ubiquitin molecules, small regulatory proteins that tag substrates for diverse cellular fates. Ubiquitin itself is a 76‑amino‑acid protein; in chain formation one ubiquitin’s C‑terminal glycine forms an isopeptide bond with a lysine side chain on another ubiquitin. Ubiquitin has seven lysine residues (K6, K11, K27, K29, K33, K48, K63) and an N‑terminal methionine (M1). Chains can be homotypic, using a single linkage type, or heterotypic/branched, combining different linkages.

The ubiquitination process relies on the ubiquitin–proteasome system: an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase that selects substrates and catalyzes transfer. Deubiquitinating enzymes (DUBs) remove ubiquitin and remodel chains, providing reversibility and regulation.

Diversity of linkages correlates with function. K48‑linked chains often tag substrates for degradation by the 26S proteasome. K63‑linked chains participate in non‑degradative signaling, including DNA damage response, endocytosis, and inflammatory pathways. Linear (M1) chains, assembled by the LUBAC complex, promote immune signaling and NF‑κB activation. Other linkages (K11, K27, K29, K33, etc.) have roles in cell cycle control, trafficking, and signaling, frequently in specific contexts.

The topology and length of chains influence recognition by ubiquitin‑binding domains and downstream effectors. Branched and mixed chains add complexity and allow integration of multiple signals. Ubiquitination is dynamically regulated by DUBs, which trim or remove chains, enabling substrate recycling or fate changes.

Dysregulation of ubiquitination is linked to diseases such as cancer, neurodegeneration, and immune disorders. Ubiquitin signaling remains an active research area, with ongoing work on chain topology, reader proteins, and therapeutic targeting of ligases and DUBs.