COLUMBUS, Ohio – All cells in the human body – and the motions they enable, from our beating hearts to our wiggling toes – use energy generated by a molecule called ATP . Its energy is thought to be released to fuel cellular processes in only one way: when ATP's decomposition is initiated by an enzyme, a specific type of protein.
Those natural enzymes are called ATPases, and ATP's reliance on their activity makes these catalysts a desirable model for drug discovery. For example, a naturally derived ATPase that's smaller and more malleable than a protein could be designed for a precise job like directing ATP's energy toward killing cancer cells, or targeted to block the release of energy that stimulates harmful cellular processes.
Researchers at The Ohio State University have gotten one step closer to that possibility by identifying the first noncoding RNA derived from human cells that can bind to ATP. The team is looking now at that RNA's function, with hopes that its attachment to ATP resembles an ATPase function that could form the basis of a therapeutic nanoparticle.
"The concept of having a noncoding RNA function as an ATPase is still really new. No one has been able to find ATPase activity in an RNA yet," said senior study author Peixuan Guo , Sylvan G. Frank Endowed Chair professor in the Division of Pharmaceutics and Pharmacology at Ohio State.
"Many scientists think human proteins handle all of the ATP activity in the body, but I think there's no way it's limited to only a protein function," he said.
The study was published recently in the journal Non-coding RNA Research .
Guo is a pioneer in the discovery of functional noncoding RNAs – tiny RNA molecules lacking instructions for building proteins – that constitute over 98% of the human genome. His lab has spent years refining nanoparticle technology with versatile RNA molecules that cooperate with the body, most recently designing molecular clusters called RNA micelles that deplete metastatic colorectal cancer tumors in mice.
He is optimistic that there is a noncoding RNA to be found in the genome that functions as an ATPase, and foresees making use of such a molecule for a new class of therapeutic nanomaterials.
This new work builds on previous work in Guo's lab that led to the identification of a viral RNA that could bind to ATP.
"I was essentially doing a continuation of that study, looking to see if there's anything in human RNAs that can bind to ATP," said first author Margaret Bohmer , a PhD student in Guo's lab.
Bohmer ran multiple rounds of screening total RNA extracted from human cells, looking for segments that could connect with ATP. She removed non-binders between rounds and amplified the presence of ATP until she had an enriched pool of RNAs that bound only to ATP. She then sequenced what was left, confirming identification of a single noncoding RNA that made a strong attachment to ATP.
The structure of this RNA is called a G-quadruplex, which has an advantage of being very compact and highly stable, Bohmer said.
The team is following up by investigating the mechanism of exactly how this noncoding RNA binds to ATP.
There's a decent chance, she said, that this noncoding RNA could be part of an ATPase motor that assists in decomposing ATP – a prediction based on the lab's previous finding that the viral RNA they found years ago that bound to ATP was part of the ATPase complex of the motor .
In another recent Non-coding RNA Research paper, Guo's team also found evidence that the same family of viral molecules, which are called packaging RNAs, or pRNAs, structurally changed over the course of evolution to perform motor-related biological functions – a sign that they, like enzyme proteins, could trigger similar catalytic reactions in cells.
"We are curious to see if this G-quadruplex RNA is an RNA that functions in a similar way," Bohmer said.
This work was supported by the National Institutes of Health, an Ohio State President's Research Excellence Catalyst Award and an Ohio State Center for RNA Biology Fellowship.
Kai Jin, a PhD student in Guo's lab, was also a co-author of the paper.
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