Development of innovative methods for regulating protein concentration using the ubiquitin-proteasome system

Effective proteolysis of a folded protein by the proteasome requires the presence of an unstructured region in the substrate in addition to a polyubiquitin chain. Here, we propose two methods of regulating substrate-specific proteasome-mediated protein degradation by regulating the unstructured region of the protein. First, we show that degradation rates can be regulated by modulating the unstructured initiation region by the binding of modifier molecules, in vitro and in vivo. These results suggest that artificial modulation of proteasome initiation is a versatile method for conditionally inhibiting the proteasomal degradation of specific proteins. Second, we develope adapter proteins that deliver specific proteins containing effective unstructured initiation sites to the proteasome. Using this method, we succeed in inducing degradation of the mutant huntingtin protein, which contains an abnormally expanded polyglutamine tract.