Structure Of Amino Acid Transporter Involved in Cancer Decoded
Scientists at the Groningen University have discovered that ASCT2, a member of the amino acid transporter family, holds great potential in increasing the growth of cancer cells in the breast. Using a cryo-electron microscopy, they were able to closely study the structure of the protein through 3-D imaging.
According to the report, ASCT2 protein transporter imports the amino acid glutamine in many tissues, thereby promoting the balance of amino acids in every cell. As the demand for glutamine increases in each cell, the amount of ASCT2 also increases. Consequently, the ASCT2 transporter becomes the docking point of various pathogenic retroviruses that are mostly cancer-causing.
This is a surprising discovery and the very first in the history of their studies with amino acids. According to Slotbottom, there are several mutagenic studies about amino acid transporters that are parallel with theirs and the consistency in the results strengthens the accuracy of their research findings.
To gain a deeper understanding of how this family of amino acid transporter performs, the scientists expressed the human gene ASCT2 in yeast cells while the human proteins were purified for imaging. Cristina Paulino, an Assistant Professor of Structural Biology and the head of the University’s Cryo-EM unit set the cryo-electron microscope’s resolution to 3.85A, which enabled her to discover an outstanding new insight. “The subject was incredibly small for the cryo-EM, which makes it very challenging but we did it,” Paulino says.
The study aims to help design drugs that will block the transport of glutamine through ASCT2 in order to prevent cancer-causing pathogens to linger in the cells.
ASCT2’s Lift Structure through the Cryo-Electron Microscope
Through the cryo-EM images, the scientists have discovered a familiar lift-structure in which the protein travels up and down through a cell membrane. “In the upper portion, you’ll see the substrate entering into the lift and moving down to release the substrate inside the cell,” Paulino explains. “In the lower position, the protein structure was rotated way down deeper and to our surprise, the substrate exits through the same opening.”
Paulino’s group have always thought that the substrate would enter and exit through various openings in the membrane but the cryo-EM images have proven them wrong.
According to Albert Guskoy, an assistant professor in crystallography, “Blocking glutamine is probably the best way to kill cancer cells and the research will help them design more rational cancer cell inhibitors.”
There have been several experiments of blocking the transport of glutamine in small mice that showed promising results but the scientists are yet to perform a series of tests to support their conclusion.
At present, PhD student Alisa Garaeva, the first author of the paper is making sure that the research will run smoothly.
Future studies will focus on configuring different ASCT2 movements in lipid bilayers. Studying the ASCT2 in different states will help the scientists understand how this particular protein functions.