Two proteins, ATG12 and ATG5 Might Help People Developing Innovative Cancer Therapies
Scientists at The Scripps Research Institute (TSRI) have found two key subunits within a cell that helps maintaining cell health. They identified how the two proteins help create organelles. Their discoveries make people think about interfering with the formation of these organelles and lead to new therapies for cancer.
Their findings were published on the journal Nature Structural & Molecular Biology on Dec. 2, 2012. Their research was supported by National Institutes of Health (NIH) grant and funded by Japan Science and Technology Agency through the Keio Kanrinmaru Project.
Past studies have shown that several proteins involve in macroautophagy which mainly eradicate damaged cell organelles or unused proteins. This involves the formation of a double membrane around the organelle known as an autophagosome that acts like a trash bag that removes toxic materials and provides the cell with nutrition through recycling. During this process, autophagosome needs many proteins work together to execute autophagy and it breaks down large proteins, invasive pathogens, cell waste and toxic materials. Some proteases, such as ATG12, ATG5 and ATG3 play vital role in this process. In addition, 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. These proteins are linked, but no one knows why and how. “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." said Takanori Otomo, the TSRI scientist who led the effort.
They 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, they can 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. They also identified a surface on the ATG12-ATG5 conjugate that binds to ATG3, another enzyme required to attach LC3 to the lipid.
With the new finding, scientists thought maybe they could find innovative cancer treatment direction by inhibiting autophagosome formation. For example, a drug that directly inhibits ATG3 binding used in coordination with current therapies to make cancer treatments more effective, starve cancer cells and prolong therapy survival. Researchers are now doing more studies in order to clearly figure out the molecular mechanisms of each step of autophagy, which can make them develop a better idea of how to manipulate the pathway for therapeutic purposes.
However, this field is still young and there are a lot of unknowns. This work is just the beginning.