Parkin and ubiquitylation of cellular substrates

National Institute On Aging

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Abstract

Parkin is a cytoplasmic protein-ubiquitin E3 ligase that is proposed to be involved in regulation of a number of cellular substrates. We have proposed that one potential substrate is phospholipase C and in recent work we have shown that disruption of phospholipase C signaling in cells leads to altered calcium homeostasis. Such phenomena can be triggered by loss of parkin or by high level overexpression of mutant forms of the protein. Given that it is a cytoplasmic enzyme, one of the more surprising results in recent years is that parkin is involved in mitochondrial function. This implies a link between parkin and other genes for recessive parkinsonism, particularly the kinase PINK1. We have also characterized some of the mitochondrial phenotypes in fibroblasts with parkin mutations. We found that these cells have mutliple correlated mitochondrial phenotypes, including altered mitochondrial membrane potential, enzyme activities and morphological changes. How this relates to ubiquitin addition to proposed substrates, the known biochemical activity of parkin, is unclear and future work will be directed at understanding this relationship.