Ubiquitin-Proteasome Pathway

1. Ubiquitin-Proteasome Pathway Ubiquitin is a 9 kDa regulatory protein which attaches to substrate proteins to form a post-translational modification, ubiquitination. The long poly-ubiquitin chains are targeted for the degradation of the 26S proteasome. The 26S proteasome, composed of 19S subunits to either side of the 20S subunit, is the proteolytic machinery associated with the ubiquitin pathway. It should be emphasized that the specificity of ubiquitination is largely determined by a series of E3 enzymes and E3 multiprotein complexes, each of which is specific to one or a few corresponding protein substrate(s) and of E2 enzymes, each of which is dedicated to their cognate E3 enzyme(s). As a result, different combinations of E2 and E3 enzymes allow selective tagging and degradation of specific intracellular proteins. In contrast, there is a single family of E1 that is highly conserved. The protein Ubc13 is a member of the Ub-conjugating (E2) enzyme family that receives Ub from E1 enzyme. Once the protein substrate is mono-ubiquitinated, a poly-ubiquitin chain is formed through the same ubiquitination conjugation cascade, in which the carboxyl group of the carboxy-terminal Gly-76 of ubiquitin is covalently linked to an internal Lys residue of ubiquitin that is already conjugated to the protein substrate. TNFα induces receptor-interacting protein kinase (RIP) poly-ubiquitination, and ubiquitinated RIP associates with NEMO (NF-κB essential modulator) to activate inhibitors of nuclear factor kappa B (IκB) kinase complex which is formed by IKKα and IKKβ. This results in the ubiquitination of IκB, and ubiquitinated IκB is separated from NF-κB and directed to the 26S proteasome, which is facilitated by valosin-containing peptide (VCP). NF-κB is released to the nucleus to activate the transcription of target genes. https://www.creative-diagnostics.com/ubiquitin-proteasome-pathway.htm