Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists at Scripps Research Institute discover how 2 proteins help keep cells healthy

03.12.2012
The work has implications for cancer drug development

Scientists at The Scripps Research Institute (TSRI) have determined how two proteins help create organelles, or specialized subunits within a cell, that play a vital role in maintaining cell health. This discovery opens the door for research on substances that could interfere with the formation of these organelles and lead to new therapies for cancer.

The study, published online ahead of print on December 2, 2012, by the journal Nature Structural & Molecular Biology, focuses on the structure and function of the two proteins, ATG12 and ATG5. These proteins need to bond correctly to form an organelle called the autophagosome, which acts like a trash bag that removes toxic materials and provides the cell with nutrition through recycling.

"Our study focuses on one of the big mysteries in our field," said Takanori Otomo, the TSRI scientist who led the effort. "These proteins are linked, but no one has explained why clearly. We're very excited to have determined the structure of these linked proteins so that the information is available to do the next level of research."

Asking Questions, Finding Answers

At the beginning of the study, Otomo and colleagues knew that many proteins work together to form autophagosomes as part of the process known as autophagy, which breaks down large proteins, invasive pathogens, cell waste, and toxic materials. As part of this process, one key protein, LC3, attaches to a lipid, or fat molecule, on the autophagosome membrane. Yet LC3 cannot attach to a lipid without the help of ATG12 and ATG5, and a cell will only form an autophagosome if the linkage, or conjugate, between these two molecules has been established.

Otomo and colleagues set out to determine the shape of the ATG12-ATG5 conjugate, and to find out why it was needed for LC3 lipidation.

Using a method called X-ray crystallography, the scientists were able to unveil the details of this conjugate. When ATG12 and ATG5 come together, they form a rigid architecture and create a surface area that is made up of evolutionarily conserved amino acids and facilitates LC3 lipidation. The researchers confirmed this finding by mutating those conserved amino acids , which prevented an autophagosome from forming.

Otomo and colleagues also identified a surface on the ATG12-ATG5 conjugate that binds to ATG3, another enzyme required to attach LC3 to the lipid.

Toward Better Understanding and New Cancer Treatments

With this new knowledge, the researchers hope to design molecules that inhibit autophagosome formation, a direction of research that has implications for cancer treatment. A drug that directly inhibits ATG3 binding, for example, could be used in coordination with current therapies to make cancer treatments more effective, preventing a cancer cell from recycling nutrients and prolonging its survival.

"Ultimately, we'd like to understand the molecular mechanisms of each step of autophagy," he said, "As we make progress toward this goal, we will have a better idea of how to manipulate the pathway for therapeutic purposes. This field is still young and there are a lot of unknowns. This work is just the beginning."

In addition to Otomo, authors of the paper, "Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy," include Chinatsu Otomo and Zoltan Metlagel of TSRI, and Giichi Takaesu of Keio University in Tokyo, Japan.

This research was supported by National Institutes of Health (NIH) grant GM092740 and by funds from Japan Science and Technology Agency through the Keio Kanrinmaru Project.

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Satellite-based Laser Measurement Technology against Climate Change

17.01.2017 | Machine Engineering

Studying fundamental particles in materials

17.01.2017 | Physics and Astronomy

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>