Findings Could Open New Pathway for Disease Treatment
By Mark Dwortzan
Messenger ribonucleic acid, or mRNA, is typically comprised of a single strand of nucleotides encoding genetic information that the cell uses to make proteins, which perform most of the work in cells and are essential to the well-being of the body’s tissues and organs. The mRNA molecules tend to fold back on themselves, forming hairpin and loop structures which must be constantly unwound in order to allow the mRNA to transmit its onboard genetic information to the rest of the cell so it can manufacture proteins.
At the heart of this process is an mRNA enzyme called eIF4A, which makes it possible for the mRNA molecules to unwind and thus for cell proteins to be synthesized. Now a team of researchers at Boston University and McGill University led by Associate Professor Amit Meller (BME, MSE) has published a study in the journal Structure that sheds light on how eIF4A gets the job done.
Using a highly-sensitive microscope that can track biomolecular activity at the single-molecule level, they discovered that it takes about one second for eIF4A to unwind 10-12-nucleotide-long mRNA hairpins, and that the mRNA transitions very quickly between wound and unwound states. In addition, they determined that a small organic molecule called hippuristanol can block eIF4A from unwinding the mRNA, by “locking” the enzyme in a closed position.
“Quantifying the molecular processes leading to and controlling protein synthesis in the cell at the single-molecule level will undoubtedly lead to new insights on this complex system,” said Meller. “Furthermore, many human diseases, including cancers and neurodegenerative diseases, are associated with abnormal levels of eIF4A and its associated proteins, so our work could open up new avenues for better understanding and treating these diseases.”
The researchers next plan to investigate a set of proteins that work with eIF4A to unwind mRNA, and quantify the effect of those proteins on the enzyme’s activity. Their work has been funded by the Human Frontier Science Program.