CELL DEATH PROTEINS KEY TO FIGHTINING DISEASE
Melbourne researchers
have uncovered key steps involved in programmed cell death, offering new
targets for the treatment of diseases including lupus, cancers and
neurodegenerative diseases
The research teams
from the Walter and Eliza Hall Institute worked together to discover the
three-dimensional structure of a key cell death protein called Bak and reveal
the first steps in how it causes cell death. Their studies were published in Molecular
Celland Proceedings of the National Academy of Sciences.
Programmed cell death,
known as apoptosis, occurs naturally when the body has to remove unwanted
cells. Chemical signals tell the cell to die by activating the apoptosis
proteins Bak and Bax, which break down the 'energy factory' of the cell, known
as the mitochondria. When this process goes awry, defective cells such as
cancer cells can continue to live, or healthy cells can die unnecessarily, such
as occurs in Alzheimer's disease.
Visualizing death
proteins
Using the Australian
Synchrotron, Mr Jason Brouwer, Dr Peter Czabotar, Dr Ruth Kluck and colleagues
from the institute's Structural Biology division investigated how the structure
of Bak changes in order to initiate cell death. The research was published in Molecular
Cell.
"Understanding
the way cell death proteins work and what they look like is crucial to finding
new ways to treat disease," Dr Czabotar said. "Our research showed
how Bak morphs from one shape to another to trigger apoptosis. Once Bak becomes
'activated' within the cell, it couples with another Bak molecule to form a
'dimer', which then goes on to initiate apoptosis."
Dr Czabotar said
understanding apoptosis would allow researchers to develop new ways to treat
disease. "Knowing the structure of these proteins and how they work in the
cell is essential in designing new treatments to fight disease."
Seeking the hole story
Dr Dana Westphal, Dr
Kluck, Dr Grant Dewson, Professor Jerry Adams and colleagues from the Molecular
Genetics of Cancer and Cell Signalling and Cell Death divisions examined how
the Bak and Bax dimers attach to mitochondria and perforate them. The research
was published in Proceedings of the National Academy of Sciences.
Dr Kluck said dimers
of Bak and Bax break open the mitochondrial surface, but the mechanism remains
poorly understood. "A crucial stage of apoptosis is the release of key
proteins from within the mitochondria," she said. "Scientists thought
this happened by Bak and Bax poking through the mitochondrial membrane to form
a hole, but our work has shown this doesn't happen. Instead, these proteins
collapse onto the oily surface of the mitochondria and crowd the surface until
holes form."
"We and others
are now working to discover exactly how these proteins come together to destroy
the mitochondria and trigger apoptosis. A deeper understanding of this pivotal
event is likely to suggest new ways to regulate apoptosis to combat
disease."
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