Deadly combination: New direct trigger for cell death discovered

Date:
January 13, 2022
Source:
University of Cologne
Summary:
Understanding the basic mechanisms that lead to cell death
(apoptosis) is essential for the development of therapies for
cancer and other diseases.

Scientists have now discovered a protein interaction that directly
triggers cell death.



FULL STORY ========================================================================== Scientists led by Professor Ana J. Garcia-Saez at the CECAD Cluster of Excellence for Aging Research at the University of Cologne have shown
that apoptosis, the programmed cell death, involves a direct physical
interplay between the two proteins BAX and DRP1. DRP1 can serve as a
direct cell death activator by binding to BAX without the need for other
cell death triggers.

This finding could lead to the development of new cell death regulators
for cancer therapies, for example. The article, 'DRP1 interacts directly
with BAX to induce its activation and apoptosis' was published in The
EMBO Journal.


==========================================================================
It is known that the so-called 'apoptotic enforcer protein' BAX
encounters DRP1 in the cell at the mitochondrial membrane. The latter
is a dynamin-like protein that plays a critical role in mitochondrial
division. However, the functional implications of their interaction and
the contribution of DRP1 to apoptosis have been highly controversial.

BAX is a key protein in the pathway to cell death. Understanding the
mechanism of action of BAX is critical for therapeutic regulation of
apoptosis. Using super-resolution confocal fluorescence microscopy and biochemical as well as biophysical methods in model membrane systems,
the research team was able to demonstrate the direct interaction of
the two proteins in dying cells. In addition, using a system that
artificially brings the two proteins together, they investigated the
functional consequences of the interaction of BAX and DRP1.

"When we artificially force the interaction of the two proteins, they
move from the cytoplasm to the mitochondria, where the protein complex
triggers a reorganization of the mitochondria. This leads to pores in
the membrane. The contents of the mitochondria enter the cell plasma,
which ultimately leads to cell death," said Andreas Jenner, first author
of the study.

By combining methods such as the dimerization-dependent fluorescence
technique, cross-linked mass spectrometry and the analysis of different
protein pieces, the interaction surface could also be identified for
the first time. DRP1 binds to the front end (N-terminus) of the amino
acid chain of BAX, which is shown to be a regulatory region for BAX
activity. 'It was impressive to see that cells started to die just by
forcing the interaction between BAX and DRP1, without the need for another death trigger,' Garcia-Saez said. 'It's great that we now know that DRP1
can act as a direct apoptosis activator, which for the first time gives functional significance to the connection between the two proteins.

This could pave the way for the development of new BAX regulators
for therapeutic applications." Work for this study began at the IFIB (Interfaculty Institute of Biochemistry) in Tu"bingen, Germany, and
was completed at the CECAD Research Center, Institute of Genetics,
in Garcia-Saez's laboratory.

========================================================================== Story Source: Materials provided by University_of_Cologne. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Andreas Jenner, Aida Pen~a‐Blanco, Raquel
Salvador‐Gallego,
Begon~a Ugarte‐Uribe, Cristiana Zollo, Tariq Ganief, Jan
Bierlmeier, Marcus Mund, Jason E Lee, Jonas Ries, Dirk Schwarzer,
Boris Macek, Ana J Garcia‐Saez. DRP1 interacts directly
with BAX to induce its activation and apoptosis. The EMBO Journal,
2022; DOI: 10.15252/embj.2021108587 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220113111451.htm
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