In the Pocket: RNA Binding Discovery Supports ‘RNA World’ Theory of Early Life on Earth

RNA biologists at the University of Rochester Medical Center (URMC) have discovered that RNA, the chemical cousin of DNA, can bind two metabolites (small molecules) at the same time in a single binding pocket, causing those molecules to interact. This discovery, published in Nature Communications this week, could lead to new antibacterial drugs while helping to fill a gap in the controversial “RNA world” theory, which suggests that RNA molecules enabled life to evolve on Earth 3.5 billion years ago.  

The RNA World

In general, all living things today rely on three main molecules to survive, grow and reproduce. DNA stores genetic information. Proteins carry out the functions necessary to keep cells healthy. But RNA can do a little of both, which suggests it may have evolved first, carrying out the main functions of early cells without the help of DNA or proteins.

That’s the crux of the RNA world theory, but this theory is not universally accepted.

“There are a lot of holes in the RNA world theory – and a lot of support for it,” said Joseph E. Wedekind, Ph.D., professor of Biochemistry and Biophysics at URMC and a lead author of the study. “For an RNA world to exist, RNA needs to be able to copy itself, which requires binding to other molecules and catalyzing reactions. Our study explained a much more efficient way for RNA to do this.”

Wedekind and his lab examined specialized sections of messenger RNA (mRNA), called riboswitches, that regulate gene expression by binding small metabolites. When a metabolite binds the riboswitch, it causes the mRNA to change shape, making certain sections of the mRNA more or less accessible to be translated into proteins.

Typically, riboswitches only bind one metabolite to set this process in motion or sometimes they can bind two metabolites located far away from one another. Wedekind and lead author Griffin Schroeder, a doctoral candidate of Biochemistry and Molecular Biology at URMC, are the first to describe a riboswitch that must bind two metabolites in a single binding pocket in order to regulate gene expression.  

They also found that the two binding molecules interact with one another cooperatively, meaning that when one molecule binds to the riboswitch, it facilitates binding of the second. Wedekind and Schroeder speculate that this finding could answer some questions about how RNA evolved the ability to catalyze reactions (something proteins usually do) and make copies of themselves.

“This is a very elegant and efficient way for RNA to bind two molecules so they can react with one another,” said Wedekind. “This could provide clues as to how early RNA could position two substrates in one pocket to promote covalent bonds – possibly to create new strands of RNA – or to simply facilitate the chemical processes required for life.”

While the pair don’t imagine their discovery will banish debate about the RNA world theory, they believe it provides a bit more support for the idea that RNA kick-started life.

Beyond Theory

The team’s discovery may have more practical near-term applications. Because the class of riboswitches the lab examined only exists in bacteria and is important for bacterial growth, they believe it can be exploited to create new antibacterial drugs that won’t cross-react with human molecules.

Designing a small molecule that can fill the riboswitch pocket and prevent proper gene regulation could gum up the bacterial works and prevent them from reproducing in human cells. As more bacteria that have these riboswitches (like Neisseria gonorrhoeae, which causes gonorrhea, and Haemophilus influenza, which causes a range of illnesses from ear infections to very serious blood infections) become resistant to current antibiotics, this could be a lifesaver.

Read the full study in Nature Communications.