Cell death proteins key to fighting disease

October 31, 2014 by Alan Gill, Walter and Eliza Hall Institute of Medical Research
Cell death proteins key to fighting disease
Mr Jason Brouwer and colleagues showed how key proteins change shape to initiate cell death.

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 called Bak and reveal the first steps in how it causes cell death. Their studies were published in Molecular Cell and 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 . 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.

Visualising 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 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."

Cell death proteins key to fighting disease
Dr Dana Westphal and colleagues found key cell death proteins don't pierce through the mitochondrial membrane as previously thought.

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."

Explore further: Immune cell death defects linked to autoimmune diseases

More information: Jason M. Brouwer, Dana Westphal, Grant Dewson, Adeline Y. Robin, Rachel T. Uren, Ray Bartolo, Geoff V. Thompson, Peter M. Colman, Ruth M. Kluck, Peter E. Czabotar, Bak Core and Latch Domains Separate during Activation, and Freed Core Domains Form Symmetric Homodimers, Molecular Cell, Volume 55, Issue 6, 18 September 2014, Pages 938-946, ISSN 1097-2765, dx.doi.org/10.1016/j.molcel.2014.07.016.

"Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane." PNAS 2014 111 (39) E4076-E4085; published ahead of print September 16, 2014, DOI: 10.1073/pnas.1415142111

Related Stories

Immune cell death defects linked to autoimmune diseases

January 23, 2013
Melbourne researchers have discovered that the death of immune system cells is an important safeguard against the development of diseases such as type 1 diabetes, rheumatoid arthritis and lupus, which occur when the immune ...

Researchers uncover powerful new class of weapons in the war on cancer

October 22, 2014
An interdisciplinary team of researchers from the University of Texas Medical Branch, and Winship Cancer Institute of Emory University have identified small molecules that can represent a new class of anticancer drugs with ...

Recommended for you

Bioprinting bone substitute materials with cell-laden bioinks

August 21, 2018
Bone tissue engineering (BTE) is a developing field in materials science and bioengineering, in which researchers aim to engineer an ideal, bioinspired material to promote assisted bone repair. Since experimental strategies ...

High-speed atomic force microscopy reveals clock protein interactions

August 21, 2018
For the first time, researchers have seen how proteins involved in the daily biological clock interact with each other, helping them to further understand a process tied to numerous metabolic and eating disorders, problems ...

Could vitamin B3 treat acute kidney injury?

August 20, 2018
Acute kidney injury, an often fatal condition without a specific treatment, affects up to 10 percent of all hospitalized adults in the United States and 30-40 percent in low-income countries. The condition causes a build-up ...

New assay to detect genetic abnormalities in sarcomas outperforms conventional techniques

August 20, 2018
Sarcomas are rare tumors that are often misdiagnosed. Specific recurrent chromosomal rearrangements, known as translocations, can serve as essential diagnostic markers and are found in about 20 percent of sarcomas. Identification ...

Team develops new way to grow blood vessels

August 17, 2018
Formation of new blood vessels, a process also known as angiogenesis, is one of the major clinical challenges in wound healing and tissue implants. To address this issue, researchers from Texas A&M University have developed ...

New imaging technique can spot tuberculosis infection in an hour

August 16, 2018
Guided by glowing bacteria, researchers have devised an imaging technique that can diagnose live tuberculosis in an hour and help monitor the efficacy of treatments. That's particularly critical because many TB strains have ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.