Sensing and clearing the damage: structural insights into the regulation of PINK1 and Parkin

Identification: Trempe, Jean-Francois


Description

Sensing and clearing the damage: structural insights into the regulation of PINK1 and Parkin
 
Jean-François Trempe1*
1Dept of Pharmacology & Therapeutics, McGill University
      
Mutations in Parkin and PINK1 cause an early-onset autosomal recessive form of Parkinson's disease (PD). PINK1 is a kinase that acts as a sensor of mitochondrial damage and initiates Parkin-mediated quality control. Recruitment and activation of Parkin by PINK1 leads to the ubiquitination of outer mitochondrial membrane proteins and subsequent autophagic clearance of the damaged organelle. Indeed, PINK1 phosphorylates both ubiquitin and Parkin on its ubiquitin-like (Ubl) domain at Ser65.  Parkin is auto-ibhibted in the basal through a series of interdomain interactions (Trempe et al. Science, 2013). Phospho-Ub binds to Parkin with high affinity and releases the Ubl through an allosteric mechanism. This enables PINK1 to phosphorylate the Ubl, which in turn increases the affinity of Parkin for E2 ubiquitin-conjugating enzymes (Sauvé et al., EMBO J, 2015).  More recently, we have shown how Parkin performs mitophagy via a distinct series of activation steps, starting with recruitment to pre-phosphorylated ubiquitin chains on mitochondria all the way to Parkin auto-inhibition release that include release of the Repressor Element of Parkin (REP) and catalytic domain RING2 (Tang et al. Nat Commun, 2017). However, what triggers PINK1's activity, and how Parkin selects its substrate(s), remain unclear.
 
My lab has been addressing these questions using structural and proteomics tools. We discovered that PINK1 auto-phosphorylation at Ser228 occurs only in trans, and is a pre-requisite to ubiquitin and Parkin phosphorylation (Rasool et al. in revision). This property provides a sensitization mechanism to prevent premature initiation of mitophagy. Moreover, we show that the first target of PINK1 consists of ubiquitin chains located on Mfn2. Finally, we investigate how the substrate specificity of Parkin is dictated by the location of phospho-ubiquitin chains, which explains why Parkin ubiquitinates primarily Mfn2 under physiological conditions. These results have implications in our understanding of PD and how we could manipulate the Parkin-PINK1 pathway to treat this disease.
 
Funding
Natural Sciences & Engineering Research Council
Canadian Institute of Health Research
Michael J Fox Foundation for Parkinson Research
Parkinson Canada

Credits

Credits: None available.

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