Arrestin‐3 interacts with Parkin mutants linked to Parkinson’s disease

Abstract

Arrestins are multifunctional proteins that were originally identified as suppressors of G protein‐coupled receptors signaling. Later arrestins were found to serve as adapter molecules that bind numerous signaling proteins, such as protein kinases, ubiquitin ligases, deubiquitinases, etc. Here, we showed the direct interaction with arrestin‐3 and parkin, which is a ubiquitin E3 ligase that covalently attaches ubiquitin to specific substrates, including mitochondrial proteins. Parkin is essential for mitophagy – the removal of damaged mitochondria. Many mutations in parkin are linked to familial or sporadic Parkinson’s disease. We identified several binding hot spots on both arrestin‐3 and Parkin using high throughput peptide arrays. Some pathogenic parkin mutations map to these arrestin‐binding hot spots. One of the pathogenic mutations, R275W, significantly increased parkin binding to arrestin‐3 in cells, as compared to wild type parkin. Our data indicate that arrestin‐3 may participate in parkin‐mediated physiological processes that likely contribute to Parkinson’s disease.Support or Funding InformationThis work was supported by grant R35 GM122491 from the National Institutes of Health to VVG.