DISCOVERY OF A NEW ROLE FOR PINK1: PHOSPHORYLATION OF UBIQUITIN BY PINK1 ACTIVATES PARKIN. Issue 10 (9th September 2014)

• Record Type: Journal Article
• Authors: Kazlauskaite, A; Kondapalli, C; Gourlay, R; Campbell, DG; Ritorto, MS; Hofmann, K; Alessi, DR; Knebel, A; Trost, M; Muqit, M
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 85:Issue 10(2014)
• Page Start: e4
• Page End: e4
• Publication Date: 2014-09-09
• Subjects: EPILEPSY; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2014-309236.38
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Mutations in the PINK1 and Parkin genes are associated with autosomal-recessive Parkinson's disease. PINK1 encodes a mitochondrial localized protein kinase and Parkin encodes an ubiquitin E3 ligase. Several lines of evidence indicate that the enzymes encoded by these genes function in a common signalling pathway. For example patients bearing mutations in PINK1 or Parkin share a similar phenotype. We have previously reported that PINK1 is activated by mitochondrial depolarization and stimulates Parkin activity by phosphorylating Serine 65 (Ser65) that lies within its ubiquitin-like (Ubl) domain. In a screen for novel PINK1 substrates we unexpectedly identified an ubiquitin phosphopeptide phosphorylated at Ser65. We undertook a series of biochemical experiments that provide striking evidence that Ser65-phosphorylated ubiquitin functions as a critical activator of Parkin. We also provide evidence that optimal activation of Parkin is dependent on PINK1-mediated phosphorylation of both Parkin at Ser65 and ubiquitin at Ser65. Our study defines PINK1 as the first ubiquitin kinase and suggests that small molecules that mimic Ser65-phosphorylated ubiquitin could hold promise as novel therapies for Parkinson's.