Protein damage, repair and proteolysis

Abstract

Proteins are continuously affected by various intrinsic and extrinsic factors. Damaged proteins influence several intracellular pathways and result in different disorders and diseases. Aggregation of damaged proteins depends on the balance between their generation and their reversal or elimination by protein repair systems and degradation, respectively. With regard to protein repair, only few repair mechanisms have been evidenced including the reduction of methionine sulfoxide residues by the methionine sulfoxide reductases, the conversion of isoaspartyl residues to L-aspartate by L-isoaspartate methyl transferase and deglycation by phosphorylation of protein-bound fructosamine by fructosamine-3-kinase. Protein degradation is orchestrated by two major proteolytic systems, namely the lysosome and the proteasome. Alteration of the function for both systems has been involved in all aspects of cellular metabolic networks linked to either normal or pathological processes. Given the importance of protein repair and degradation, great effort has recently been made regarding the modulation of these systems in various physiological conditions such as aging, as well as in diseases. Genetic modulation has produced promising results in the area of protein repair enzymes but there are not yet any identified potent inhibitors, and, to our knowledge, only one activating compound has been reported so far. In contrast, different drugs as well as natural compounds that interfere with proteolysis have been identified and/or developed resulting in homeostatic maintenance and/or the delay of disease progression.

Keywords: 4-hydroxynonenal; AD; AGEs; Aging; Alzheimer’s disease; C-L; CT-L; FNK; HD; HNE; Huntington’s disease; IIS; Ins/IGF-1; Insulin/Insulin Growth Factor; Insulin/Insulin Growth Factor-1 signaling pathway; Lon protease; Lysosome; MDA; MMP; Methionine sulphoxide reductase; Msr; PD; PGPH; PIMT; Parkinson’s disease; Protein modification; RNS; ROS; Reactive oxygen species; T-L; TIMP; UPS; Ubiquitin-proteasome system; advanced glycation end products; caspase-like activity; chymotrypsin-like activity; fructosamine-3-kinase; malondialdehyde; matrix metalloproteinase; methionine sulfoxide reductase; peptidylglutamylpeptide hydrolyzing activity (or); protein L-isoaspartate methyl transferase; reactive nitrogen species; tissue inhibitor of metalloproteinase; trypsin-like activity; ubiquitin-proteasome system.