David Komander-Projects

David Komander-Projects

Researcher: 

Projects

Mechanisms of mitophagy

A highly studied form of 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 PINK1 or Parkin 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 and enzymes involved in mitophagy. We are now keen to target the system with small molecules, which may be useful to treat neurodegenerative diseases.

Schematic process of mitophagy
Protein structures in mitophagy

 

Mechanisms, functions and inhibitors of deubiquitinases

Deubiquitinases (or DUBs) are the enzymes that reverse ubiquitin signals, and hence affect all ubiquitin functions. Most importantly, the overproduction of a DUB can lead to the stabilisation of its substrates – a situation highly relevant, for example, with oncogenes, where it has been proposed that small molecule inhibitors of DUBs could initiate the removal of any protein, including so called ‘undruggables’.

We study mechanisms and regulation of DUBs at the structural, biochemical and physiological level. Uncovering the function and substrates of DUBs will be essential to provide new drug targets, and understanding their structure, mechanism and regulation enables drug discovery.

Ubiquitin drug discovery diagram
Opportunities for drug discovery in the ubiquitin system

 

New tools to enable ubiquitin studies

Any science is only as good as the tools available to study it. Our research of unstudied atypical ubiquitin signals and of ubiquitin chain architecture, require the development of new biochemical methods and reagents, which then also give the opportunity to study ubiquitination in unprecedented detail and unveil new biology. 

In particular, we have developed methods to study ubiquitin chains using linkage specific deubiquitinases (UbiCREST), and affimers that act similarly to antibodies in detecting understudied ubiquitin chain types. 

We work in close collaboration with Dr Andrew Webb to develop new tools to study ubiquitin signals by mass-spectrometry (Ub-clipping).