PathwayStep6565 PathwayStep6564 PathwayStep6567 PathwayStep6566 PathwayStep6563 PathwayStep6569 PathwayStep6568 PathwayStep6570 E1 mediated ubiquitin activation Transfer of ubiquitin from E1 to E2 Trimming of N-ter extended precursor fragments by cytosolic aminopeptidases Release of E3 from polyubiquitinated substrate Proteasomal cleavage of substrate Transfer of Ub from E2 to substrate and release of E2 Polyubiquitination of substrate Interaction of E3 with substrate and E2-Ub complex Antigen processing: Ubiquitination & Proteasome degradation Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 GENE ONTOLOGYGO:0000209 Intracellular foreign or aberrant host proteins are cleaved into peptide fragments of a precise size, such that they can be loaded on to class I MHC molecules and presented externally to cytotoxic T cells. The ubiquitin-26S proteasome system plays a central role in the generation of these class I MHC antigens. <br>Ubiquitination is the mechanism of adding ubiquitin to lysine residues on substrate protein leading to the formation of a polyubiquitinated substrate. This process involves three classes of enzyme, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. Polyubiquitination through lysine-48 (K48) generally targets the substrate protein for proteasomal destruction. The protease responsible for the degradation of K48-polyubiquitinated proteins is the 26S proteasome. This proteasome is a two subunit protein complex composed of the 20S (catalytic core) and 19S (regulatory) proteasome complexes. The proteasome eliminates most of the foreign and non-functional proteins from the cell by degrading them into short peptides; only a small fraction of the peptides generated are of the correct length to be presented by the MHC class I system. It has been calculated that between 994 and 3122 protein molecules have to be degraded for the formation of a single, stable MHC class I complex at the cell surface, with an average effciency of 1 in 2000 (Kloetzel et al. 2004, Princiotta et al. 2003). Pubmed11917093 Pubmed12648452 Pubmed14734113 Pubmed17145306 Pubmed19489725 Pubmed20351195 Reactome Database ID Release 43983168 Reactome, http://www.reactome.org ReactomeREACT_75842 Reviewed: Elliott, T, 2011-02-10