Beyond a Messenger: The 3'UTR Acts as a "Chaperone" to Help Thousands of Critical Regulatory Proteins Fold Correctly

Proteins are the workhorses of the cell. They carry out almost every vital cellular task, from transmitting signals to controlling which genes are turned on or off. For a protein to perform its diverse functions, its three-dimensional structure is theoretically dictated by its primary structure. In most cases, the specific sequence of amino acids determines a protein’s shape—how it will fold. However, the crowded environment inside a cell, combined with the large size and flexible regions of certain proteins, can lead to misfolding or aggregation. Molecular chaperones (such as heat shock proteins Hsp70 and Hsp90) are a class of proteins known to assist others in folding properly.

Now, scientists at Memorial Sloan Kettering Cancer Center (MSK) have made a fundamental discovery that challenges this textbook paradigm—revealing that this is not the case for thousands of critical regulatory proteins, the very molecules that coordinate which genes are active or silent and ultimately control cellular behavior. Published recently in the journal Cell, the lab's latest study uncovers an entirely new role for a long-overlooked region of mRNA: its "tail" end, which helps ensure these crucial regulatory proteins fold correctly.

"The conventional wisdom has been that only specialized proteins act as chaperones to help other proteins fold properly," says Dr. Christine Mayr, a member of the Sloan Kettering Institute, the basic science research arm of MSK. "Our study demonstrates that RNA can do this too, and that mRNA serves as a chaperone for its own class of important, hard-to-fold proteins."

The study was led by first author Dr. Yang Luo, a postdoctoral fellow in the Mayr Lab.

Unlocking RNA's Hidden Function

This is not the first time Dr. Mayr and her team have uncovered vital new cellular biology hiding in plain sight. In 2018, they discovered a new cellular organelle. More recently, they revealed that the liquid phase of the cell—the cytoplasm—is divided into distinct regions, each responsible for translating different types of mRNAs.

To understand their latest breakthrough, it helps to know that mRNA consists of three main components: a "coding sequence" (which contains the blueprint for the protein) sandwiched between "head" and "tail" regions that serve other functions.

"The head region is typically very small, meaning the coding sequence and the tail make up the vast majority of the RNA's total length," Dr. Luo explains.

Figure 1. mRNA 3′ UTRs control protein activity by preventing co-translational misfolding. (Luo Y, et al., 2025)

The tail of the mRNA is formally known as the 3'UTR. The "3-prime" indicates its position at the very end of the mRNA molecule, while "UTR" stands for "untranslated region," meaning it does not encode information used to build the protein sequence itself.

"For years, scientists largely ignored the 3'UTR, viewing it as unimportant," Dr. Mayr notes. "But we noticed that thousands of human 3'UTRs feature highly conserved sequences. Moreover, these patterns remain identical across vertebrates, from fish to birds to mammals. To us, this was a clear clue that they must play an important role. Biology rarely preserves things it doesn't need."

Not All Proteins Fold Easily

The new research reveals that the mRNA tail—the 3'UTR—is crucial for helping specific types of proteins fold properly.

Dr. Luo points out that small, compact proteins can usually fold well on their own. However, many larger, more complex regulatory proteins—such as the transcription factors MYC, UTX, and JMJD3—contain what scientists call "intrinsically disordered regions" (IDRs). These are long, flexible segments that do not fold into a stable structure on their own.

"Left to their own devices, these long, complex proteins contain sticky clusters of amino acids that can grab onto other parts of the protein during assembly, preventing it from folding properly," she says.

The research team discovered that cells solve this folding dilemma by producing these complex proteins within specialized compartments called "reticular condensates." These compartments act like "delivery rooms" for proteins that need extra assistance. There, as the protein is being built, the 3'UTR physically grabs onto the sticky regions, preventing them from interfering with the proper folding process.

Thousands of Proteins Require Extra Help

The scale of this phenomenon is remarkable. The team identified more than 2,700 genes with highly conserved 3'UTRs—representing roughly one-eighth of all protein-coding genes in the human genome. These genes encode proteins that contain IDRs with sticky regions, meaning they likely cannot fold correctly without the assistance of an RNA chaperone.

"Our study shows that for thousands of regulatory proteins in human cells, the genetic code alone is not enough to produce a functional protein—you also need the RNA chaperone," Dr. Mayr says.

Beyond providing new insights into fundamental biology, these findings have practical implications for laboratory research. Scientists frequently conduct experiments using only the protein's coding sequence, lopping off the 3'UTR to simplify their assays.

"For thousands of regulatory proteins, removing the 3'UTR means you are studying a misfolded, less active version of that protein," Dr. Mayr warns.

Ultimately, this work demonstrates that RNA is far more than just a passive messenger carrying genetic instructions, Dr. Luo adds. "RNA is an active participant in building proteins—providing the guidance needed to ensure they fold correctly and can function properly."