New insights into the structure of PINK1 and the mechanism of ubiquitin phosphorylation

Abstract

Mutations in PINK1 cause early-onset recessive Parkinson’s disease. This gene encodes a protein kinase implicated in mitochondrial quality control via ubiquitin phosphorylation and activation of the E3 ubiquitin ligase Parkin. Here, we review and analyze functional features emerging from recent crystallographic, nuclear magnetic resonance (NMR) and mass spectrometry studies of PINK1. We compare the apo and ubiquitin-bound PINK1 structures and reveal an allosteric switch, regulated by autophosphorylation, which modulates substrate recognition. We critically assess the conformational changes taking place in ubiquitin and the Parkin ubiquitin-like domain in relation to its binding to PINK1. Finally, we discuss the implications of these biophysical findings in our understanding of the role of PINK1 in mitochondrial function, and analyze the potential for structure-based drug design.

Keywords:

• PINK1
• kinase
• phosphorylation
• ubiquitin
• Parkin
• Parkinson’s disease
• structure
• mitochondria

Acknowledgments

We would like to thank members of the Trempe, Gehring, and Fon labs for interesting discussion, and in particular Mr Luc Truong for help with nucleotide-binding analysis. We acknowledge support from the Canada Research Chair Program, Parkinson Canada, the Michael J. Fox Foundation, the Natural Science & Engineering Research Council of Canada, as well as the Canadian Institute of Health Research.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

1 For the sake of simplicity, in our analysis we will largely refer to residue numbering/positioning in TcPINK1. The residue numbering for PhPINK1 will be referenced as well while discussing conformational changes, autophosphorylation and the structure of inserts 2 and 3.