ENYZMES AFFECTING THE ACCUMULATION OF ALTERED PROTEINS

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DESCRIPTION: (Adapted from the Application). The manifestations of aging result in part from cells becoming less efficient at self-repair with time. These reactions represent one part of the battle of organisms to maintain the structural integrity of essential macromolecules in the face of the molecules intrinsic instabilities. Defects in these mechanisms may underlie pathologies where the aging process can be accelerated. The objective of this work is to understand how aging organisms prevent the accumulation of covalently altered proteins that can compromise cellular functions. These investigators will characterize the role of the protein L-isoaspartate (D-aspartate) O-methyltransferase that recognizes spontaneously-damaged proteins and catalyzes the initial step of a protein repair reaction. The discovery of this pathway reveals that macromolecular repair may not be just for DNA, but for proteins as well. These investigators propose to ask how the potential accumulation of damaged proteins in aging is reduced by methylation and other pathways in viva. They will utilize model organisms including bacteria, yeast, worms, and plants. Specifically, we will characterize protein damage in the bacterium Escherichia coli. They will study mutant phenotypes of both the methyltransferase pcm gene and the sure gene shown to be present in an operon with pcm. They will also study the role of associated enzymes that are involved in the metabolism of isoaspartyl-containing proteins and peptides, including isoaspartyl dipeptidases. They will analyze mutants of the protein repair methyltransferase in the nematode worm Casnorhabditis elegant. They will ask how the yeast Saccharomyces cerevisiae can avoid the accumulation of proteins containing altered aspartyl residues in spite of the fact that it naturally lacks the methyltransferase. Finally, they will examine the role of the methylation reaction in controlling protein damage in higher plants, including corn and Arabidopsis. These studies will hopefully not only provide a new window to view protein life but may also suggest that the biological aging process may be closely linked to how well cells can keep polypeptides free of spontaneous covalent damage.