Zombieland: evolution of a dead enzyme that kills cells by necroptosis

Zombieland: evolution of a dead enzyme that kills cells by necroptosis

Project details

Six years ago a catalytically dead ‘pseudokinase’, MLKL was identified as the terminal effector in the necroptosis cell death pathway. MLKL-mediated cell death is triggered upon its phosphorylation by the protein kinase RIPK3, although the underlying mechanism remains of outstanding interest. 

Our recent findings indicate some important differences in mechanism of activation between mouse and human MLKL (Petrie et al., Nat Comm 2018), which warrants further detailed investigation to understand how necroptotic mechanisms might have evolved divergently in different species. 

This project will study MLKL evolution using cellular systems, including CRISPR-edited cell lines, and purified proteins by structural biology, mass spectrometry and biophysical methods (such as SPR, ITC), to enhance our molecular level knowledge of how MLKL is triggered to kill cells.

About our research group

Our lab is interested in the protein interactions that underlie signal transduction in our cells. These studies draw on diverse methodologies, including structural biology and biophysics, cellular and molecular biology, and mass spectrometry, to understand these processes at the molecular level.

We are especially interested in how cell signalling is controlled by 'zombie' proteins (pseudokinases), which look like active protein kinases but lack catalytic functions.

 

Researchers:

Dr Emma Petrie profile shot
Dr
Emma
Petrie
Cell Signalling and Cell Death division

Project Type:

Our research has revealed the structure of a protein that triggers a form of programmed cell death called necroptosis