Why ‘Lab-made’ Proteins Can Take The Heat

According to researchers from Japan, the unique backbone of lab-made proteins makes them more tolerant to high temperatures.

AsianScientist (Jan. 5, 2021) – Compared to their counterparts found in nature, proteins built entirely from scratch tend to be more tolerant of high temperatures, found bioengineers from Japan. Their discovery was published in the Proceedings of the National Academy of Sciences.

Over the years, naturally thermostable proteins—or proteins that are stable at high temperatures—have been widely applied across research and industry. Take for instance the polymerase chain reaction (PCR), perhaps molecular biology’s central technique, which relies on the eponymous Taq polymerase. Due to its ability to withstand temperatures of up to 95°C, the Taq polymerase enables the repeated amplification of genetic material—with variations of PCR proving crucial to the fight against COVID-19.

Given their significance, it comes as no surprise that protein thermostability has literally become one of biotechnology’s hottest topics. Typically, researchers tweaked existing natural proteins to enhance their thermostability. However, it is difficult to modify natural proteins without altering their function. Hoping to avoid this, some protein engineers have turned to building proteins entirely from scratch—a process called de novo protein design.

“For some reason, de novo proteins have repeatedly shown increased tolerance in the face of quite high temperatures compared to natural proteins,” said study co-author Associate Professor Nobuyasu Koga from Japan’s Institute for Molecular Science. “Where others would [break down], the lab-made proteins are still working just fine well above 100°C.”

To uncover the mystery behind the high thermostability of lab-made proteins, the team analyzed de novo proteins they had previously designed. According to Koga, these proteins were specifically engineered to have a tightly-packed, water-resistant core. Choosing those with the highest thermostability, Koga and his colleagues then began to tweak ten amino acids that contribute to the tightly-packed core.

As they modified the proteins, the team observed that there was little reduction in their overall thermostability. This suggests that it is unlikely that the protein’s core influences thermostability. Instead, Koga and his colleagues propose that the backbone structure probably plays a larger role.

“Hydrophobic tight core packing may not even be very important for designed proteins,” added study co-author Dr. Rie Koga from the Exploratory Research Center on Life and Living Systems (ExCELLS). “We can create an exceptionally stable protein even if the core packing is not so optimized.”

With these considerations in mind, the team intends to explore how the protein backbone can be further altered without compromising its thermostability in future studies.

The article can be found at: Koga et al. (2020) Robust Folding of a De Novo Designed Ideal Protein Even With Most of the Core Mutated to Valine.


Source: National Institutes of Natural Sciences; Photo: Shutterstock.
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