Fatal attraction: how apoptotic pore assembly is governed during mitochondrial cell death

Fatal attraction: how apoptotic pore assembly is governed during mitochondrial cell death

Project details

As the formation of BAX and BAK homo-oligomers strongly correlates with their ability to perforate mitochondria, defining how BAX and BAK dimers self-associate and interact with the membrane will reveal how they trigger apoptosis.

Our data indicate that dimers do not interact by distinct protein-protein interface, but form disordered clusters to generate pores (Uren, eLife, 2017;6:e19944; Uren, Philos Trans R Soc Lond B Biol Sci, 2017 Aug 5;372(1726). pii: 20160218).

A range of well-established biochemical approaches will be paired with cutting-edge imaging technologies to examine further how the mitochondrial outer membrane influences the clustering of BAK and BAX dimers.

About our research group

The Kluck lab investigates how cells die via a process called apoptosis. Apoptotic cell death is a normal process that helps remove excess or damaged cells. When apoptotic cell death goes wrong, the results are often cancer or autoimmune diseases.

We are interested in the proteins inside cells that orchestrate apoptosis, in particular how two pore-forming BCL-2 family members, BAX and BAK, undergo a major conformation change and generate pores in the mitochondrial outer membrane. The goal of our research is to identify new means of specifically regulating apoptotic cell death in cancer and other diseases. 

We have found that both BAX and BAK form unusual symmetric homodimers that are the basic unit of the apoptotic pore (Uren, Philos Trans R Soc Lond B Biol Sci, 2017 Aug 5;372(1726). pii: 20160218). To determine how dimers form clusters that disrupt the membrane, we employ  protein chemistry and structural approaches. To specifically address the role of the membrane in driving clusters and pore formation, we are collaborating with Niall Geoghegan at the Centre for Dynamic Imaging at the Institute to quantify changes in the mitochondrial membrane before and after pore formation.

We also discovered that BAK can be activated by antibodies (Iyer, Nat Commun. 2016 7:117342). With our collaborators, we are engineering alternative antibody formats to determine whether antibodies can be delivered into cancer cells to directly trigger BAK-mediated apoptosis.

Researchers:

Dr Rachel Uren prophile image
Dr
Rachel
Uren
Blood Cells and Blood Cancer division

Project Type: