How mRNA Gets Its Final Shape

Proteins must interact in a complex way to create so-called “informational RNA” (mRNA) in human cells from a precursor molecule. mRNA provides a protein plan; the first coronavirus vaccines were also based on mRNA. A team from Martin Luther University in Halle-Wittenberg (MLU) and the Max Planck Institute for Biochemistry (MPI) in Martinsried found out how an important last step in mRNA production works. The study is published in the journal Genes & Development.

Proteins are responsible for all the necessary processes in the body. In a sense, genes in the human genome act for them as building blocks. However, an intermediate step is needed before new proteins can be created: “DNA needs to be transcribed first: a stranded RNA precursor is formed, which is an exact copy of DNA. To create a mature protein you need to follow a few steps. mRNA. This process is necessary to create new protein cells, ”says biochemist Professor Elmar Val of MLU, who led the group along with Professor Elena Conti, an expert in structural biology at MPI Biochemistry.

There is no room for error in this complex process – even the smallest changes in the structure of the protein can impair its function and lead to disease. “MRNA determines not only the structure of a protein, but also how much it is produced. Therefore, it is important that its structure is also closely monitored,” adds Val. The proteins involved in reading and transcribing DNA into an RNA precursor are already known to scientists. However, an important sub-step in the process of creating mature mRNA has so far only been vaguely understood. First, the strands of mRNA precursors are cleaved at a certain point to create homogeneous products. A long molecular chain, called a poly (A) tail, is then attached to one end of the thread. This ensures that mRNA is not broken down directly in cells, and this is also important for protein synthesis.

Researchers from Gale and Martinsried have joined forces to more closely investigate these latest steps in mRNA production. To do this, the team from MLU first resumed the in vitro process. Scientists had to select the right proteins from a pool of 80 possible candidates. They had to be mixed with the RNA precursor in the right proportions before both reactions could occur. Researchers with MPI have studied this process in more detail using cryoelectron microscopy. “We basically lost the conditions in a normal cell, although the natural process is probably even more complicated,” Vale explains. Sixteen proteins are involved in making the final molecules. “The process is universal, affecting every cell and every mRNA molecule in the body,” says Felix Sandmeyer of MPI Biochemistry.

On the other hand, the process used to make Pfizer / Biontech and Moderna vaccines is much simpler: “mRNA is created on the same principle, but unlike human cells, very simple enzymes are used and complex conversion of the precursor to mature mRNA can be avoided.” says in conclusion Wall.

Help: Schmidt M., Kluge F., F. Sandmeyer et al. Restoration of 3’-end mammalian pre-mRNA processing shows a central role for RBBP6. Genes Dev. 2022. DOI: 10.1101 / gad.349217.121
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