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Microscope images of dying HeLa cell. Top: Healthy cell with Bax (green) in the cytosol, mitochondria are intact (violet). Bottom: Dying cell, Bax has attacked the mitochondria. @Bleicken

#Asktheauthor: How proteins regulate cell death

3 Questions to RESOLV scientist Stephanie Bleicken about her recent Nature Communications publication on programmed cell death.

 

1. What is the new discovery that you made?

We focused our research on three Bcl-2 type proteins that cooperate in programmed cell death (the so-called apoptosis): The proapoptotic Bax protein (involved in the opening of pores in the outer membranes of mitochondria), the proapoptotic cBid (activates Bax) as well as the prosurvival Bcl-xL (inhibits Bax). We discovered that the interactions between these proteins strongly change if they are in solution or in membranes. For example Bcl-xL associates with cBid both in solution and membrane, while Bcl-xL binds to Bax only in membrane. 

2. What is its significance?

Apoptosis is a kind of cell suicide program to remove infected, damaged, overaged, or unneeded cells from our body - a vital process. Apoptosis initiation needs to be tightly regulated or severe illnesses like cancer or auto-immune diseases as well as neurodegenerative ones can be induced. The Bcl-2 protein family has a key function in executing and regulating apoptosis, that´s why these kind of proteins are an attractive target for drug development.

However, the current knowledge on Bcl-2 interactions is mainly limited on studies in solution. Tackling protein interactions in membranes is much more difficult and therefore less understood - but it is exactly in the mitochondrial membrane that apoptosis regulation kicks-off. We were able to target the protein interactions both in membranes and in solution by using the same technique, Fluorescence-cross-correlation-spectroscopy (a microscope-based method). This approach was crucial to compare the two environments.

We sumarize our results into a new model that integrate the knowledge from previous models that were considered controversal. This is a significant step towards understanding cell death, yet we have to deepen our knowledge before being able to manipulate this vital process.  

3. Is this related to Solvation Science? If yes, how?

Yes. We studied protein-interactions in two different environments, or, in other words, in two different solvents. In our case, moving from the hydrophilic cytosol to the hydrophobic membranes changed the protein interactions drastically, a clear example of solvent effect in biology.

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