lysine48

Lysine-48, commonly abbreviated as Lys-48 or K48, is a lysine residue at position 48 in ubiquitin, a small regulatory protein that tags other proteins for various fates within the cell. Lys-48 is the site through which polyubiquitin chains are most often assembled to signal proteasomal degradation.

In ubiquitination, ubiquitin molecules are linked through isopeptide bonds between the C-terminal glycine of a donor ubiquitin and the ε-amino group of Lys-48 on the preceding ubiquitin in the chain. Lys-48-linked polyubiquitin chains are the best-characterized signal directing substrates to the 26S proteasome, where they are recognized by ubiquitin receptors, leading to substrate unfolding and degradation.

Lys-48 chains are one of several linkage types formed on ubiquitin, and their formation is mediated by a variety of E2 conjugating enzymes in cooperation with E3 ligases. Deubiquitinases can specifically disassemble Lys-48 linkages, thereby reversing the degradation signal or editing ubiquitin chains to alter substrate fate.

Biological significance of Lys-48–linked chains lies in protein quality control and regulated turnover. They play a central role in removing misfolded, damaged, or regulatory proteins to maintain cellular homeostasis. Misregulation of Lys-48–linked ubiquitination has been implicated in several diseases, including cancer and neurodegenerative disorders, highlighting the importance of tightly controlled ubiquitin signaling.

Detection and study of Lys-48 linkages employ linkage-specific antibodies and mass spectrometry, enabling researchers to quantify and characterize the abundance and regulation of Lys-48–linked polyubiquitin in cells and tissues.