Proteosomal Degradation

Proteosomal Degradation Prothrombin Time Protocadherins Protocidal Drugs... 

Hsp90 is a molecular chaperon required for the refolding of proteins in cells exposed to environmental stress. It contains an ATP-binding pocket in its amino terminus. Several natural products, for example radicicol (230) (Scheme 48), bind to this pocket and inhibit its chaperon function, which is mirrored in enhanced proteosomal degradation of Hsp90 client proteins, so that compounds like 230 are of interest as novel anticancer agents. 

Proteosome An enzyme complex that degrades intracellular proteins. 

Proteins which are destined for degradation by the proteosome are first modified by the enzyme-catalysed attachment of numerous molecules of the protein ubiquitin, through amino groups to the protein targeted for degradation. This marks out the protein for ATP-dependent hydrolysis by the 26S proteosome, releasing peptides and ubiquitin... 

Iwai etal, 1995 Guo etal, 1995). It seems therefore highly probable that the proteosome (and also ubiquitinylation) is involved in IRP-2 degradation. 

VON DEE Lehr, N. et al. The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol Cell 2003, 33, 1189-200. 

FIG. 5. Role of phosphorylation and degradation of clock protein PER in human normal fibroblasts. After the phosphorylation of hPERl by casein kinase, the ubiquitin-proteosome pathway may be involved in its degradation in human cells. 

Fig. 2.15A. Pattern of ubiquitinylation of proteins and degradation in the proteosome. Ubiquitin (Ub)is initially activated by an enzyme El, whereby the C-terminal carboxyl group of ubiquitin becomes attached to a SH group of El via a thioester bond. Ubiquitin is then transferred from El-Ub to E2, from which it is transferred with the help of E3 to the target protein. Several ubiquitin molecules can attach to the target protein in a hnear or in a crosshnked fashion. The mono- or polyubiquitinylated protein is degraded to peptides in the 26S proteosome. In the above diagram the filled circles represent the ubiquitin residues attached to the target protein. K lysine residues of the target protein.

Fig. 2.17. Degradation of the tumor suppressor protein p53 by the ubiquitin-proteosome system. The oncoprotein E6 of the human papilloma virus (HPV) forms a specific complex with the p53 protein and can thus induce the degradation of p53. The E6-p53 complex is recognized by E6-AP, a E3 enzyme of the ubiquitin pathway, as a target protein, whereby a ubiquitin residue is transferred to a lysine residue of p53. In this process, the E6 protein serves as the recognition element for ubiquitin hgation of p53.

Extracellular barriers (DNA, enzymes, mucus) Paucity of receptors Proteosome-mediated degradation Inhibition of second-strand synthesis Airway clearance, anti-inflammatory, anti-protease pre-treatments Alternate serotypes, targeted capsid mutants Proteosome inhibitors (tripeptides, anthracyclines) Tyrosine kinase inhibitors... 

Yi Law, Horace Low, and colleagues. Similar to other G-protein-coupled receptors, upon the activation of delta receptor by its agonists, the receptor molecule can be internalized and degraded through endosomes, lysosomes, and proteosomes some receptors may recycle back to the cell surface. Molecular components responsible for receptor trafficking have also been fully studied and documented in the literature. 

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