New Insights into How Cells Fine-Tune Protein Assembly

Imagine the body as a bustling factory constantly assembling proteins, the building blocks that keep everything running smoothly. These proteins are made from amino acids, delivered by specialized trucks called transfer RNA (tRNA) to the protein-building machines, the ribosomes.

New EMBL Grenoble Kowalinski Group research sheds light on a fascinating collaboration within this factory. The researchers discovered how one enzyme uses another's structure as a scaffold to recognize and efficiently process these tRNA deliveries, ensuring the smooth flow of protein assembly.

The Kowalinski group at EMBL Grenoble has shed new light on the mechanism that guarantees that these tRNA delivery trucks are optimized for their tasks using a combination of structural biology techniques.

The group investigated tRNA modification enzymes, a class of specialized molecular laborers that can "personalize" these tRNA delivery vehicles. They add or modify specific tRNA structural elements that improve the precision and efficiency of the protein-building process. As a result, proteins are produced more precisely and reliably since the tRNA trucks are optimized for their specific roles.

The question is how the tRNA modification enzymes precisely select which tRNA molecules to modify, making sure they do not pick the incorrect ones. Although all tRNA molecules have a similar appearance, the enzymes can only work with specific types of tRNA.

The Kowalinski group conducted experiments to address this, and the results have now shown how one such tRNA modification enzyme, known as METTL6, chooses its particular tRNA target.

Scientists can use a potent method known as cryo-electron microscopy to see the minute details of proteins. Here, the scientists quickly freeze the protein to capture it in its unaltered, native three-dimensional form. Then, they employ an electron beam to produce shadows that mirror the protein's three-dimensional structure, much like a spotlight.

We use these shadows to compute the shape and structure of the protein. We used this technique to reveal the structure of METTL6 together with its target tRNA."

Luciano Dolce, Postdoc, EMBL

Researchers discovered that the tRNA modification enzyme METTL6 interacts with a different enzyme called "tRNA synthetase" rather than acting alone.

The workers in the above analogy are called tRNA synthetases, and their job is to load the tRNA delivery vehicles with the appropriate amino acids. Every tRNA delivery truck has a unique code or pattern that corresponds to a code on the building site. tRNA synthetases are extremely intelligent enzymes that can decipher the tRNA trucks’ nucleotide code, locate the appropriate amino acid, and load it.

The researchers discovered that the tRNA modification enzyme METTL6 is not very specific or effective when working alone. Rather, METTL6 uses the assistance of its astute companion, serine tRNA synthetase. This particular tRNA synthetase binds tRNAs that encode serine, a type of amino acid.

The serine tRNA is much easier to distinguish from other tRNAs when it is bound to the serine tRNA synthetase enzyme. Consider serine tRNA synthetase as METTL6’s wise advisor when it comes to determining which tRNA to alter. This friendship, according to the study’s authors, is the first instance of a tRNA-modifying enzyme that uses tRNA synthetase as a recognition factor.

This finding is equivalent to discovering a potent new tool for creating more effective medications rather than merely figuring out the structure of the METTL6–serine tRNA synthetase complex bound to tRNA. This is especially crucial since cancer patient tumor samples, such as those from certain liver and breast malignancies, contain a high concentration of METTL6.

Studies on mice and cell cultures indicate that METTL6 downregulation may aid in inhibiting the spread of cancer. The Kowalinski Group’s latest research elucidates the mechanism of action and tRNA recognition of METTL6. This will make it possible to create precise medications to stop the growth of tumors, which could prove to be a more effective tactic in the ongoing fight against diseases as it stems from knowledge of the molecular mechanisms underlying the body.