The E3 ubiquitin ligase Parkin and mitophagy in Parkinson’s disease

The E3 ubiquitin ligase Parkin and mitophagy in Parkinson’s disease

Project details

Mitophagy - a cellular process that leads to the destruction of damaged mitochondria by autophagy - is regulated by phosphorylated ubiquitin, and uncharacterised Lys6-linked ubiquitin chains. These specialised ubiquitin signals are generated by the ubiquitin kinase PINK1 and the ubiquitin E3 ligase Parkin. Importantly, mutations of Parkin or PINK1 lead to inherited forms of early-onset Parkinson’s disease.
 
In the past five years, we have provided a detailed molecular description of the ubiquitin signals generated by the PINK1 and Parkin enzymes involved in mitophagy (Gladkova et al, Nature 2018, 559(7714)410; Schubert et al, Nature 2017, 553(7683)51). We are now keen to target the system with small molecules, which may be useful to treat neurodegenerative diseases such as Parkinson’s disease.

This project will involve multiple molecular and cell biology techniques including protein chemistry, structural biology, tissue culture.

 

About our research group

Ubiquitination most commonly leads to destruction of the modified protein, but can also change its activation, interactions or localisation. The labs of the Ubiquitin Signalling division (Komander, DewsonFeltham, Lechtenberg) focus on understanding the essential role of ubiquitin in cellular signalling pathways and in pathologies including inflammatory disease, cancer and neurodegeneration.

In the Komander lab, we focus on the modifier ubiquitin, a small protein that modifies other proteins in a variety of distinct ways, known as the ‘ubiquitin code’.

A biological focus of the Komander lab is E3 ligases that catalyse the addition of ubiquitin onto target porteins and deubiquitinases (DUBs) that remove ubiquitin. We use structural biology and biophysics, to unravel many mechanistic and regulatory principles of how E3s and DUBs modify proteins with ubiquitin.

Using preclinical models and in collaboration with human geneticists, we ascribe cellular and physiological function to select enzymes. Finally, in collaboration with industry, we are developing the first enzyme-specific DUB inhibitors, which may become new treatments for cancer and neurodegeneration. 

Further reading:
Gladkova C, Maslen S, Skehel LM, Komander D. Mechanism of Parkin activation by PINK1. Nature. 2018 Jul;559(7714):410-414. Epub 2018 Jun 6.
Schubert AF, Gladkova C, Pardon E, Steyaert J, Maslen SL, Komander D. Structure of PINK1 in complex with its substrate ubiquitin. Nature. 2017 Dec 7; 552(7683): 51-56.

 

Email supervisors

 

Researchers:

Project Type: