A highly specific and regulated intracellular process that functions to recognize, tag, and break down many proteins in eukaryotic cells. In this process a protein is tagged for degradation through covalent ligation to ubiquitin (q.v.), followed by degradation by the 26S proteasome (q.v.). The conjugation of ubiquitin to the substrate protein (ubiquitination) occurs in multiple steps. First, the C-terminus (q.v.) glycine residue of ubiquitin is activated by the enzyme E1 in an ATP-requiring step. Activated ubiquitin is then transferred to one of several E2 enzymes (ubiquitin-carrier proteins or ubiquitin-conjugating enzymes). Ubiquitin is further transferred from E2 to an E3 enzyme belonging to the ubiquitin-protein ligase family. Finally, the E3 enzyme catalyzes the covalent linkage of ubiquitin to the substrate protein. The specificity of ubiquitin-protein conjugation is dependent on the recognition of particular signals on the substrate protein by the appropriate E3 enzyme. The attachment of a ubiquitin molecule to the target protein is usually followed by the formation of a polyubiquitin chain, which is then recognized by the 19S regulatory particle of the proteasome. The protein is unfolded and translocated to the central cavity of the proteasome, the 20S core complex, where it undergoes ATP-dependent degradation. The resulting peptides, 8-9 amino acids long, leave the proteasome and enter the cytosol where peptidases break them down further. Ubiquitin monomers are also released for future use by the activity of deubiquitinating enzymes (q.v.). Ubiquitin-mediated protein degradation is important for eliminating defective proteins. Furthermore, through the highly selective and regulated targeting of a wide range of substrate proteins, UPP controls numerous cellular functions, including cell-cycle progression, cellular signal transduction (q.v.), and regulation of transcription (q.v.). UPP has also been linked to apoptosis (q.v.) and to the processing of many MHC class 1 antigens. Many pathological conditions are associated with abnormalities in ubiquitin-mediated processes. See Chronology, 1980, Hershko et al.; otu, retinitis pigmentosum (RP), SUMO proteins.
Subjects: Genetics and Genomics.