Biochemistry researchers at the University of Illinois Urbana-Champaign are conducting trailblazing work on a group of conserved proteins that are directly related to abnormal cell proliferation and developmental and neurological disorders. In a new article published in Cell Reports, biochemistry professor Hong Jin and her team have deciphered the function of developmentally-related GTPase (Drg) proteins which are crucial to life.
Ribosomes are responsible for synthesizing proteins by translating mRNA into an amino acid sequence. Researchers have been studying Drg proteins for approximately 30 years. While a lot of discoveries regarding their interactions have been made, the detailed function of the protein is unknown.
“The hallmark of life is making new proteins,” said Jin when describing why she became interested in Drg1. “We study protein synthesis, ... how our cells make proteins that are in demand, and when and where the protein is made. Existing literature shows that Drg1 actually binds to the ribosome, which is the central machinery in every living cell on this planet that makes protein.
Jin and her lab employed high-throughput 5P-sequencing to gain insights into the function of Drg1 protein at a genomic scale. They also utilized an in vitro biochemistry method to study Drg1 protein function in a controlled environment.
However, according to Jin, the most impactful method they used in their study was electron cryo-microscopy (cryo-EM). This technique allowed Jin and her colleagues to reconstruct the three-dimensional structures of Drg1 bound to the ribosome. Each atom of this macromolecular structure could be visualized through cryo-EM.
“From here, it really opens up a whole new field of study at the molecular level where we can further dissect the mechanisms of translational control of Drg1,” Jin explained.
Often during translation, a ribosome will pause, leading to the stall of protein synthesis. Stalling can either be resolved so that synthesis may continue, or the entire translational system can be disintegrated. From her functional analysis, Jin found that Drg1 works to identify the stalled ribosome and reorganize it so that the ribosome may continue protein synthesis. This highly conserved protein plays a fundamental role in the biology of our cells and is critical for the restoration of translational activity in the cell.
Watch a video explaining the process.
“This work was spearheaded by a very talented postdoc from my lab, Dr. Fuxing Zeng, now followed up by a group of fantastic students in my lab,” Jin said. Zeng is now tenure-track assistant professor with his own research group in China.
Understanding the functional role of Drg1 can be applied to many developmental or neurological disorders. For example, Drg, and many of its translation factors, are overexpressed in cancer cells. A hallmark of cancer is uncontrolled growth. Because of the fundamental role of proteins in translation, Drg1 could act as a target to inhibit the growth of cancer cells. As researchers continue to uncover the mechanisms of Drg1, this could lead to potential clinical treatments.
Jin’s groundbreaking work on Drg1 has probed a host of new research questions regarding the functional mechanisms of Drg proteins. Fundamental research on a highly conserved protein like Drg1 can help researchers develop a better understanding of the mechanisms of translational control, protein synthesis, and cellular life as a whole.
Fundamental research “is not something that can quickly be used to treat cancer...or disease, but [instead] to understand a phenomenon that is related to all life, not just one cell, not just a human, [but] every living organism on this planet,” Jin said.
