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mRNA Tails Play Key Role in Folding Regulatory Proteins
mRNA 3′ UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. In a new study published in Cell titled, “mRNA 3′ UTRs chaperone intrinsically disordered regions to control protein activity,” researchers from Memorial Sloan Kettering (MSK) Cancer Center now demonstrates that mRNA 3′ UTRs play a key role assisting the folding of regulatory proteins.
“The traditional view is that only specialized proteins act as ’chaperones’ to help other proteins fold correctly,” said Christine Mayr, MD, PhD, a member of the Sloan Kettering Institute and corresponding author on the paper. “Our research shows that RNA can do this, too—and that mRNAs act as their own chaperones for a group of important, hard-to-fold proteins.”
While 3′ UTRs have traditionally been dismissed as key regulators, Mayr emphasizes that thousands of human 3′ UTRs have highly conserved sequences across vertebrates, offering a clue of their function. “Biology doesn’t usually preserve things that aren’t needed,” she says.
Many larger, complex regulatory proteins, such as the transcription factors MYC, UTX, and JMJD3, possess long, flexible regions, named intrinsically disordered regions (IDRs), that do not fold into stable structures on their own.
The study showed that cells solve this folding problem using specialized compartments, known as mesh-like condensates. The 3′ UTR promotes IDR–IDR interactions and suppresses folding between domains. Results suggest that this chaperone activity prevents interference between hydrophobic clusters in the IDR with folding of the structured domain.
The team identified more than 2,700 genes with highly conserved 3′ UTRs, or about one in every eight protein-coding genes in the human genome. The proteins expressed by these genes contain intrinsically disordered regions that require RNA chaperones to facilitate folding.
“What we show is that for thousands of regulatory proteins in human cells, the genetic code alone isn’t enough to make a functional protein—you need the RNA chaperone too,” said Mayr.
The study has practical implications for laboratory research. For thousands of regulatory proteins, removing the 3′ UTR allows researchers to study the misfolded, and less active version of the protein.
The post mRNA Tails Play Key Role in Folding Regulatory Proteins appeared first on GEN – Genetic Engineering and Biotechnology News.
Hosted by Drug Discovery World and supported by Sartorius and BioIVT, this webinar will explore the opportunities and challenges that exist within cancer research drug discovery and development.
You will hear from Dr Sudha Rao, Chief Scientific Officer of Kazia Therapeutics, Karol Budzik, PhD, Business Development Associate at Vyriad Therapeutics and Lars van der Veen, Chief Scientific Officer at iOnctura.
Presentations will cover how cancer treatments have shifted towards reprogramming the biology driving tumour growth, immune escape and treatment resistance, the trajectory that in vivo CAR-T treatments are taking, and how challenging tumours burdened by stroma and immune-mediated resistance can be tackled.
Q&A with the speakers follows the presentations.
The post New webinar: Tackling drug discovery challenges in cancer research appeared first on Drug Discovery World (DDW).
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New Spectrometry Technique Could Aid Formulation Development
New Spectrometry Technique Could Aid Formulation Development
A new technique combining two forms of spectrometry could help biopharmaceutical companies improve their choice of formulation buffer for antibody manufacturing by revealing how molecular forms and three-dimensional shapes of complex biologics respond to their environment. That’s the view of Christian Bleiholder, PhD, a professor at Florida State University who helped develop the technique.
According to Bleiholder, what happens structurally when a complex biological molecule, such as an antibody or viral spike protein, binds to its target is currently poorly understood.
“This is where [this approach] can help with the bioprocessing and formulation,” he says, as structural changes “can affect the lifespan [of the product] and lead to issues, such as aggregation.”
Because antibodies are complex, existing techniques tend to be powerful at different levels of complexity, he explains. Mass spectrometry is particularly powerful for distinguishing molecular composition, while structural approaches such as X-ray crystallography and cryo-electron microscopy can provide high-resolution structural information.
The challenge is understanding the link between these things within a heterogeneous sample, he says.
To overcome this, Bleiholder and his team worked with Bruker Daltonics to develop Tandem-Trapped Ion Mobility Spectrometry (Tandem-TIMS). This combines tandem ion mobility spectrometry with tandem mass spectrometry to disentangle three overlapping layers of molecular complexity: molecular form, three-dimensional shape, and binding or assembly state, he says.
He explains that, if the proteins have different structures, they can be characterized with tandem ion mobility spectrometry, and then mass spectrometry can be used to look at their molecular forms and binding states.
Going forward, Bleiholder hopes the technique can be used for formulation development but also earlier, during drug discovery of new products, such as multi-specific antibodies, to determine which molecular states are important and how those change when a biologic engages its target. He also plans to look at automating the technique.
Bleiholder spoke about using Tandem-TIMS at the Bioprocessing Summit in Boston earlier this year.
The post New Spectrometry Technique Could Aid Formulation Development appeared first on GEN – Genetic Engineering and Biotechnology News.
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