K48mediated

K48mediated refers to ubiquitination events in which polyubiquitin chains are assembled through lysine 48 of ubiquitin, a modification that commonly signals proteasomal degradation. In this pathway, ubiquitin is activated by E1 enzymes, transferred to E2 enzymes, and then conjugated to substrate proteins by E3 ligases in a substrate-specific manner. Chain elongation favors the formation of K48-linked polyubiquitin, which is recognized by the 19S regulatory particle of the 26S proteasome, leading to substrate unfolding and degradation.

K48-mediated ubiquitination is contrasted with other ubiquitin linkage types (for example, K63-linked chains) that often regulate signaling, trafficking, or DNA repair rather than proteolysis. The degradative signal is typically robust when chains reach a sufficient length and are properly configured, though the exact requirements can vary among substrates and cellular contexts.

Regulation of K48-mediated ubiquitination involves deubiquitinating enzymes (DUBs) that remove K48 chains and can rescue substrates from degradation or reset ubiquitin signals. The process is also subject to cellular control by proteasome availability, adaptor proteins, and signaling pathways that influence E3 ligase activity.

K48-mediated ubiquitination has broad biological relevance, governing protein turnover during the cell cycle, stress responses, and development. Dysregulation of this pathway is linked to diseases such as cancer and neurodegeneration, and pharmacological inhibition of the proteasome or of specific E3 ligases can modulate K48-mediated degradation for therapeutic purposes.