The protein L-isoaspartyl methyltransferase (PIMT) is well known for its protein repair function, namely the reconversion of deamidated and/or isomerized asparaginyl and aspartyl residues (L-isoaspartyl residues) into their normal, non-isomerized forms. The conversion of biomolecules to non-useful and potentially toxic products by unwanted chemical reactions represents probably an important aspect of the aging process in living organisms. To the extent that they can minimize the accumulation of damaged molecules, they can endure. PIMT knockout mice accumulate high levels of damaged proteins in their tissues, especially the brain, and die of massive seizures at an average age of 42 days. On the other hand, worms and flies overexpressing this enzyme live longer, strongly suggesting a role for PIMT in the aging process. A particularly intriguing observation is that the insulin/IGF-1 signaling pathway is activated in the brain of PIMT knockout mice. Genetic evidence also exists for an interaction between PIMT and insulin-like signaling in Caenorhabditis elegans. It has recently become clear that insulin-like signaling plays an important role in the regulation of the aging process. Lowered insulin/IGF-1 signaling, especially in neuronal tissues, leads to lifespan extension in worms, flies and mice. The overall objective of this project is to understand the link between PIMT and insulin-like signaling. A first aim is to consolidate the interaction between PIMT and insulin-like signaling in worms. A second aim is to analyze the effect of PIMT deficiency on the phosphoproteome of mouse brains. A third aim is to elucidate the mechanism by which PIMT deficiency leads to the observed changes in protein phosphorylation. Several routes, including direct regulation of protein phosphatase activity by PIMT methylation, modulation of such an activity by a critical isoaspartyl residue, and effect of high isoaspartyl content in a protein on its phosphorylation state will be explored.
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