Lys48

Lys-48, often written Lys48, is a lysine residue at position 48 in ubiquitin, a small, highly conserved regulatory protein found in eukaryotes. When ubiquitin molecules are linked through Lys48, they form Lys48-linked polyubiquitin chains, created when the C-terminal glycine of one ubiquitin forms an isopeptide bond with the ε-amino group of Lys48 on the next ubiquitin. Lys48-linked chains are the canonical signal for targeting substrates to the 26S proteasome for degradation.

The formation of Lys48-linked chains is driven by the ubiquitin activation and conjugation cascade—E1 activates ubiquitin, E2 carries it, and E3 ligases confer lysine-specific linkage to substrates. Deubiquitinases can remove or remodel Lys48 chains, reversing or modulating the degradation signal.

Biophysical studies indicate Lys48-linked chains adopt a compact, globular conformation that is distinct from the more extended arrangements seen in Lys63-linked chains. This structural difference contributes to selective recognition by the proteasome, guiding substrate processing and degradation.

Functionally, Lys48-mediated ubiquitination regulates protein turnover, with broad roles in cell cycle control, quality control, and stress responses. Proper control of Lys48-linked degradation is essential for cellular homeostasis, and dysregulation has been linked to diseases such as cancer and neurodegenerative disorders. Lys48 is one of several lysine linkage options in ubiquitin, each generating different cellular signals and outcomes.