Molecular Biology Research

Understanding Programmed Cell Death

16. 9. 2015 | Researchers from the University of Tübingen, headed by Prof. Ana García-Sáez, studied membrane pores that are crucial for starting apoptosis.
When cells age or suffer damage, they are able to bring about their own pre-programmed death – a 'suicide' programme known as apoptosis. Desensitization towards this process can change a cell from a normal cell into a cancer cell. On the other hand, an over-functioning of apoptosis is associated with the onset of neurodegenerative diseases. Therefore a better understanding of the underlying mechanisms is extremely important. The protein Bax is known as a key regulator of apoptosis.

Prof. Ana García-Sáez
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Prof. Ana García-Sáez
A research collaboration headed by Prof. Ana García-Sáez of the University of Tübingen, and Professor Joachim Spatz of the Max Planck Institute for Intelligent Systems in Stuttgart, have investigated the role of Bax proteins, finding more detailed information as to how they work. The key step in apoptosis is the release of the protein Cytochrome c and other apoptotic factors from the mitochondria into the cell interior. After this step, apoptosis is irreversible and cell's fate is sealed. In order to allow this process, the mitochondrial membrane must be permeable. The research team has examined how the mitochondrial membrane becomes permeable.

Their experiments on artificial membrane systems showed that the Bax protein initially is inserted into the membrane as a single molecule. Once inserted, this monomer instantly teams up with another Bax molecule to form a stable complex, the so-called 'Bax dimer'. From these dimers larger complexes are formed. "Surprisingly, Bax complexes have no standard size, but we observed a mixture of different-sized Bax species," says Dr. Katia Cosentino, a member of Professor García-Sáez team, "and these species are mostly based on dimer units." These Bax complexes ultimately form the pores through which Cytochrome c exits the mitochondrial membrane.

The process of pore formation is finely controlled by other proteins. Some enable the assembly of Bax-elements, while others induce their dismantling. "The differing size of the Bax complexes in the pore formation is likely part of the reason why earlier investigations on pore formation conveyed in contradictory results", explains Katia Cosentino. The researchers can now make some initial recommendations for medical intervention in the apoptotic process: In order to promote cell suicide, it should be enough to initiate the first step by activating Bax proteins – because the subsequent steps will then happen automatically. Conversely, from these new insights it can be concluded that apoptosis may be prevented when drugs dissolve the Bax dimers.

Ana García-Sáez has been a professor in Tübingen since 2013 and received an ERC Starting Grant in 2012. She had gained her PhD at the University in Valencia, Spain, where she studied biochemistry and chemistry. She completed her post-doc work at the TU Dresden in Germany, where she received a Marie Curie Intra European fellowship. Besides being a professor in Tübingen, she is a research group leader at the Max Planck Institute for Intelligent Systems in Stuttgart.
  (© University of Tübingen, AcademiaNet)
Dr. Karl Guido Rijkhoek

More information

Source

  • Yamunadevi Subburaj, Katia Cosentino, Markus Axmann, Esteban Pedrueza-Villalmanzo, Eduard Hermann, Stephanie Bleicken, Joachim Spatz and Ana J. García-Sáez: Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species. Nature Communications, 14 August 2015, doi:10.1038/ncomms9042

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