The ribosome, that protein-making machine, relies on other, smaller machines. For example, it works in concert with a mechanism that supplies amino-acid-carrying tRNAs, including tRNAs that require modification along the delivery route. Details about this mechanism have been uncovered by EMBL Grenoble scientists led by Eva Kowalinski, PhD. They used cryo-electron microscopy and other structural biology methods to determine that two enzymes—human m3C tRNA methyltransferase METTL6 and seryl-tRNA synthetase (SerRS)—work together to detect tRNAs in need of modification and ensure that the necessary modification is made. Ultimately, the enzymes ensure that selected tRNAs are optimized and tailored for their respective tasks, leading to a more reliable and precise production of proteins.

The scientists presented their findings in Nature Structural & Molecular Biology, in an article titled, “Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase.”

“Here, we report the cryo-electron microscopy structure of the human m3C tRNA methyltransferase METTL6 in complex with seryl-tRNA synthetase (SerRS) and their common substrate tRNASer,” the article’s authors wrote. “We show that SerRS acts as the tRNASer substrate selection factor for METTL6. We demonstrate that SerRS augments the methylation activity of METTL6 and that direct contacts between METTL6 and SerRS are necessary for efficient tRNASer methylation.”

Essentially, the scientists sought to answer this question: Given that all tRNA molecules look very similar, and given that the tRNA modification enzymes work only with specific types of tRNA, how do the modification enzymes precisely select specific tRNA molecules to modify, and ensure they don’t mistakenly choose the wrong ones?

To answer this, the Kowalinski group carried out experiments on the tRNA modification enzyme METTL6. For example, they used cryo-electron microscopy. It let them rapidly freeze the protein, which helped them to capture the protein’s natural 3D shape without any distortions. The technique also let them use a beam of electrons to create shadows that conveyed information about the 3D structure of the enzyme.

“We use these shadows to compute the shape and structure of the protein,” said Luciano Dolce, PhD, a postdoctoral researcher and one of the study’s lead authors. “We used this technique to reveal the structure of METTL6 together with its target tRNA.”

In the case of the METTL6 tRNA modification enzyme, the researchers figured out that it does not act on its own but interacts with seryl-tRNA synthetase.

In a manner of speaking, tRNA synthetases are like workers responsible for loading tRNA delivery vehicles with the right amino acids. Each tRNA delivery truck carries a specific code or pattern that matches with a code on the construction site. tRNA synthetases are very smart enzymes that can read the nucleotide code of the tRNA trucks and then find and load the correct amino acid that matches the code.

The scientists found that the tRNA modification enzyme METTL6 on its own is not particularly specific and not very efficient at doing its job. Instead, METTL6 takes the hand of its smart friend, the serine tRNA synthetase. This tRNA synthetase specifically binds tRNAs that carry the code for an amino acid called serine.

When the serine tRNA is bound to the serine tRNA synthetase enzyme, it is much easier to distinguish from other tRNAs. You could think of serine tRNA synthetase as a very smart friend that helps METTL6 figure out which tRNA to modify. The authors of the study believe this friendship is the first known example of a tRNA-modifying enzyme using a tRNA synthetase as a recognition factor.

This discovery is more than just figuring out the structure of the METTL6–serine tRNA synthetase complex bound to tRNA; it’s like discovering a powerful new tool for making better medicines. This is particularly important since METTL6 is highly abundant in tumor samples of cancer patients, for example, in some breast and liver cancers.

Studies in cell cultures and mice suggest that slowing METTL6 down might help reduce cancer growth. The new findings by the Kowalinski group show how METTL6 works and how it recognizes tRNA. This will enable designing precise drugs to slow down tumor growth, which may become a smarter strategy in the ongoing battle against illnesses—one that comes from understanding the inner workings of the body’s molecular machinery.

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