Proteasome constitutive

Gao, Y., Post, M. J., and Simons, M. Proline- and arginine-rich peptides constitute a novel class of allosteric inhibitors of proteasome activity. Biochemistry 2003, 42, 8663-70. 

The proteasome is a very large complex of at least 50 subunits. It is present in a wide variety of tissues and can constitute up to 1% of soluble protein in a cell. The catalysis occurs within the central core of the molecule and ATP hydrolysis is required to drive the protein into the core. Before the complex can break down proteins, the latter must first have been tagged by complexing with ubiquitin, a peptide of molecular mass 8.5 kDa. This attachment requires three enzymes and the hydrolysis of ATP and it results in a peptide link between the carboxylic group at the C-terminus of ubiquitin and the NH2 of a lysine side-chain in the condemned protein. Several ubiquitin molecules are attached to a single lysine so that a chain of four or more ubiquitin molecules is formed (Figure 8.2). It is. 

The function of ubiquitin-conjugation during endocytosis remained obscure for many years, althoi it became clear that, in contrast to ER-degradation, it did not result in degradation by the 26S proteasome (Hicke, 1999 Strous and Covers, 1999). In 1996 experiments performed in yeast pointed to a very unexpected function of ubiquitin-conjugation at the plasma membrane It constitutes a signal for the endocytosis of cell surface receptors (Hicke and Riezman, 1996). 

Human ySli, pli and y 5i subunits are 59.2%, 57.7% and 68.6% identical, respectively, with their constitutively active cotmterparts pi, pi and 5, and 46.0%, 46.0% and 57.6% identical, respectively with the pi, pi and ps subunits in yeast. Indeed, all induced subunits of the human 20S proteasome have higher sequence similarity to the corresponding subunits of the human constitutive proteasome than to their yeast counterparts. Both of the human proteasomes share the remaining four p subunits and all the a subunits. Therefore, the X-ray structure of the bovine 20S proteasome was used for more accurate prediction of the three-dimensional structure of the immunoproteasome (Fig. 3.6). 

Fig. 3.6 Structure comparison of the active centers of the constitutive proteasome with the active centers of the immunoproteasome. (a), (b) Diagrams of eiectrostatic surface po-tentiai of SI pockets for the and i active sites. Red and biue indicate negative and positive potentiais, respectiveiy. The SI pocket is surrounded by a dotted circie. The SI pocket of the p active center is formed by both and fn subunits, (a) The SI pocket of the ySl active center is charged positiveiy at the pi subunit side and negativeiy at the p subunit...

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