Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection

Abstract

Autosomal recessive forms of Parkinson’s disease are caused by mutations in three genes: Parkin, PINK1, and DJ-1. These genes encode for proteins with distinct enzymatic activities that may work together to confer neuroprotection. Parkin is an E3 ubiquitin ligase that has been shown to ubiquitinate substrates and to trigger proteasome-dependent degradation or autophagy, two crucial homeostatic processes in neurons. PINK1 is a mitochondrial protein kinase whose activity is required for Parkin-dependent mitophagy, a process that has been linked to neurodegeneration. Finally, DJ-1 is a protein homologous to a broad class of bacterial enzymes that may function as a sensor and modulator of reactive oxygen species, which have been implicated in neurodegenerative diseases. Here, we review the literature on the structure and biochemical functions of these three proteins.

Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

“…4B). The kinase domain of the obtained PINK1 structure was in good agreement with previous models (Beilina et al , 2005; Mills et al , 2008; Cardona et al , 2011; Sim et al , 2012; Trempe and Fon, 2013). In addition, our model also contained the N-terminal region that regulates import, sub-mitochondrial localization, and turnover of PINK1.…”

“…To model PINK1 protein, its dynamics and enzymatic activity, we used a combination of methods that have been applied before to predict mutational effects and activation conformations of human parkin (Caulfield et al , 2014, 2015; Fiesel et al , 2015 b ), which were in good agreement with the latest structures of an activated form of the E3 ubiquitin ligase (Kumar et al , 2015; Sauve et al , 2015; Wauer et al , 2015). The C-terminus of our PINK1 model is very similar to structures of homologous kinases and existing models of the PINK1 kinase domain (Beilina et al , 2005; Mills et al , 2008; Cardona et al , 2011; Sim et al , 2012; Trempe and Fon, 2013). …”

Mitochondrial Degradation, Autophagy and Neurodegenerative Disease

“…The role of DJ-1 in PD is less understood compared to PINK1 and Parkin, but it appears to function in the same pathway [ 89 ]. This is supported by the fact that loss of DJ-1 results in mitochondrial dysfunction and can be rescued by Parkin overexpression [ 100 ].…”

Insertion C V317rfs*75 With Frame Shift Mutation, Was Shown to Be More Frequent in Pink1 Gene in Sudanese Patients.

“…[7] Other patients of various ethnicities with early-onset PD were soon reported to also harbour PARK2 mutations with varying deletions or point mutations that cause PARK2 protein loss of function [8] PARK2 contains 12 exons that encode the 465 amino acid protein, Parkin [7]. Parkin is an E3 ubiquitin ligase with an amino-terminal ubiquitin-like (Ubl) domain and a carboxyl-terminal ubiquitin ligase domain [9]. Study done by Rasol et al, mentioned that, The PINK1/Parkin pathway is one of the best known pathways involved in mitochondrial repair and removal of damaged mitochondria [10,11] .…”