Degradation of oxidized proteins in mammalian cells.
Protein oxidation in vivo is a natural consequence of aerobic life. Oxygen radicals and other activated oxygen species generated as by-products of cellular metabolism or from environmental sources cause modifications to the amino acids of proteins that generally result in loss of protein function/enzymatic activity. Oxidatively modified proteins can undergo direct chemical fragmentation or can form large aggregates due to covalent cross-linking reactions and increased surface hydrophobicity. Mammalian cells exhibit only limited direct repair mechanisms and most oxidized proteins undergo selective proteolysis. The proteasome appears to be largely responsible for the degradation of soluble intracellular proteins. In most cells, oxidized proteins are cleaved in an ATP-and ubiquitin-independent pathway by the 20 S "core" proteasome. The proteasome complex recognizes hydrophobic amino acid residues, aromatic residues, and bulky aliphatic residues that are exposed during the oxidative rearrangement of secondary and tertiary protein structure: increased surface hydrophobicity is a feature common to all oxidized proteins so far tested. The recognition of such (normally shielded) hydrophobic residues is the suggested mechanism by which proteasome catalyzes the selective removal of oxidatively modified cell proteins. By minimizing protein aggregation and cross-linking and by removing potentially toxic protein fragments, proteasome plays a key role in the overall antioxidant defenses that minimize the ravages of aging and disease.
Grune
T
T
The Andrus Gerontology Center, University of Southern California, Los Angeles 90089-0191, USA.
Reinheckel
T
T
Davies
K J
KJ
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D008322:Mammals; D008565:Membrane Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D015388:Organelles / Q000378:metabolism; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism*; D012995:Solubility
D000596:Amino Acids; D000975:Antioxidants; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D011506:Proteins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex