By studying the structure of actin-depolymerising factor 1 (ADF1), a key protein involved in controlling the movement of malaria parasites, the researchers have demonstrated that scientists' decades-long understanding of the relationship between protein structure and cell movement is flawed.
Dr Jake Baum and Mr Wilson Wong from the institute's Infection and Immunity division and Dr Jacqui Gulbis from the Structural Biology division, in collaboration with Dr Dave Kovar from the University of Chicago, US, led the research, which appears in today's edition of the Proceedings of the National Academy of Sciences USA.Dr Baum said actin-depolymerising factors (ADFs) and their genetic regulators have long been known to be involved in controlling cell movement, including the movement of malaria parasites and movement of cancer cells through the body. Anti-cancer treatments that exploit this knowledge are under development.
"For many years research in yeast, plants and humans has suggested that the ability of ADFs to dismantle actin polymers – effectively disengaging the clutch – required a small molecular 'finger' to break the actin in two," Dr Baum said. "However, when we looked at the malaria ADF1 protein, we were surprised to discover that it lacked this molecular 'finger', yet remarkably was still able to cut the polymers. We discovered that a previously overlooked part of the protein, effectively the 'knuckle' of the finger-like protrusion, was responsible for dismantling the actin; we then discovered this 'hidden' domain was present across all ADFs."
Mr Wong said that the Australian Synchrotron was critical in providing the extraordinary detail that helped the team pinpoint the protein 'knuckle'. "This is the first time a 3D image of the ADF protein has been captured in such detail from any cell type," Mr Wong said. "Imaging the protein structure at such high resolution was critical in proving beyond question the segment of the protein responsible for cutting actin polymers. Obtaining that image would have been impossible without the synchrotron facilities."
Dr Baum said the new knowledge will give researchers a much clearer understanding of one of the fundamental steps governing how cells across all species grow, divide and, importantly, move. "Knowing that this one small segment of the protein is singularly responsible for ADF1 function means that we need to focus on an entirely new target not only for developing anti-malarial treatments, but also other diseases where potential treatments target actin, such as anti-cancer therapeutics," Dr Baum said. "Malaria researchers are normally used to following insights from other biological systems; this is a case of the exception proving the rule: where the malaria parasite, being so unusual, reveals how all other ADFs across nature work."
More than 250 million people contract malaria each year, and almost one million people, mostly children, die from the disease. The malaria parasite has developed resistance to most of the therapeutic agents available for treating the disease, so identifying novel ways of targeting the parasite is crucial.
Dr Baum said that the discovery could lead to development of drugs entirely geared toward preventing malaria infection, without adverse effects on human cells. "One of the primary goals of the global fight against malaria is to develop novel drugs that prevent infection and transmission in all hosts, to break the malaria cycle," Dr Baum said. "There is a very real possibility that, in the future, drugs could be developed that 'jam' this molecular 'clutch', meaning the malaria parasite cannot move and continue to infect cells in any of its conventional hosts, which would be a huge breakthrough for the field."
This project was funded by the National Health and Medical Research Council (NHMRC).
Liz Williams | EurekAlert!
Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard
New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University
DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.
Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...
MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.
Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
15.12.2017 | Power and Electrical Engineering
15.12.2017 | Materials Sciences
15.12.2017 | Life Sciences