INHIBITION OF THE MULTICATALYTIC PROTEINASE (PROTEASOME) BY 4-HYDROXY-2-NONENAL CROSS-LINKED PROTEIN

Oxidative modification of glucose-6-phosphate dehydrogenase (Glu-6-PDH ), as observed for other proteins, increases the susceptibility of the protein to degradation by the multicatalytic proteinase/proteasome (M CP). Oxidized Glu-6-PDH is, however, more prone to cross-linking react ions by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE), proc esses which render the protein resistant to proteolysis, In addition, HNE cross-linked protein inhibits the degradation of oxidatively modif ied glutamine synthetase by the MCP, In contrast to oxidized Glu-6-PDH , which inhibits the proteolysis of GS in a competitive manner, HNE cr oss-linked protein acts as a noncompetitive inhibitor, As judged by bi nding of the hydrophobic fluorescent probe 8-anilino-1-naphthalenesulf onic acid, a common structural feature of both macromolecular substrat es and inhibitors of the MCP is an increased accessibility of hydropho bic regions on the protein. (C) 1997 Federation of European Biochemica l Societies.