“Hero” Proteins May Shield Other Proteins from Harm in Neurodegenerative Disease

by Emma Yasinski

Researchers at RIKEN and the University of Tokyo report the existence of a new class of proteins in Drosophila and human cell extracts that may serve as shields that protect other proteins from becoming damaged and causing disease. An excess of the proteins, known as Hero proteins, was associated with a 30 percent increase in the lifespan of Drosophila, according to the study, which was published last week (March 12) in PLOS Biology.

“The discovery of Hero proteins has far-reaching implications,” says Caitlin Davis, a chemist at Yale University who was not involved in the study, “and should be considered both at a basic science level in biochemistry assays and for applications as a potential stabilizer in protein-based pharmaceuticals.”

Nearly 10 years ago, Shintaro Iwasaki, then a graduate student studying biochemistry at the University of Tokyo, discovered a strangely heat-resistant protein in Drosophila that seemed to help stabilize another protein, Argonaute, in the face of high temperatures that would denature most proteins. Although he didn’t publish the work at the time, Iwasaki called the new type of protein a Heat-resistant obscure (Hero) protein—not because of their ability to rescue Argonaute from destruction, but because in Japan, the term “hero” means “weak or not rigid,” and Hero proteins don’t have stiff 3-D structures like other proteins do.
But recognition of a more widespread role for Hero proteins in protecting other molecules in the cell gives the name new meaning.

“It is generally assumed that proteins are folded into three-dimensional structures, which determine their functions,” says Kotaro Tsuboyama, a biochemist at the University of Tokyo and the lead author of the new study. But these 3-D structures are disrupted when the proteins are exposed to extreme conditions. When proteins are denatured, they lose the ability to function normally, and sometimes begin to aggregate, forming pathologic clumps that can lead to disease.

Hero proteins can survive these biologically challenging conditions. Heat-resistant proteins have been found in extremophiles—organisms known to live in extreme environments—but were thought to be rare in other organisms. In the new study, Tsuboyama and his team boiled lysates from Drosophila and human cell lines, identifying hundreds of Hero proteins that withstood the temperature.

The researchers selected six of these proteins and mixed them with “client” proteins—other functional proteins that on their own would be denatured by extreme conditions—before exposing them to high temperatures, drying, chemicals, and other harsh treatments. The Hero proteins prevented certain clients from losing their shape and function.

Next, the team tested the effects of Hero proteins in cellular models of two neurodegenerative disorders characterized by pathologic protein clumps: Huntington’s disease and amyotrophic lateral sclerosis (ALS). When the Hero proteins were present, there was a significant reduction in protein clumping in both models.

“This is an extremely important finding as it may pave new therapeutic and preventive strategies for neurodegenerative diseases, such as Alzheimer and Parkinson diseases,” Morteza Mahmoudi, who studies regenerative medicine at Michigan State University and was not involved in the research, writes in an email to The Scientist.

Lastly, the team genetically engineered Drosophila to produce an excess of Hero proteins. These flies lived up to 30 percent longer than their wildtype counterparts.

Not everyone is convinced that the Hero proteins play a major protective role. “Although they show these proteins help their proven targets remain folded/shielded etc, I don’t think there’s a broader application at all,” Nihal Korkmaz, who designs proteins at the University of Washington Institute of Protein Design and also did not participate in the study, tells The Scientist in an email. She adds that many proteins she works with can withstand high temperatures and the researchers “don’t mention at all if [Hero proteins] are found throughout the brain or in CSF [cerebrospinal fluid],” where they’d be able to protect against Huntington’s or ALS.

The authors emphasized that there is a lot left to learn about the proteins. Each Hero protein seems able to protect some client proteins, but not all of them. Moreover, amino acid sequences differ considerably between Hero proteins, making it difficult to predict their functions. The researchers write in the study that they hope future studies will help them identify which clients each Hero might work with.

Whatever discoveries future work might hold, Tsuboyama says, the scientific community’s reaction to the team’s new study has been consistent: “Almost everyone says that Hero proteins are interesting but mysterious.”

K. Tsuboyama et al., “A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation,” PLOS Biol, doi:10.1371/journal.pbio.3000632, 2020.


Cockroach milk

The sight of cockroaches may evoke disgust but they can be a boon for human health, said a team of scientists who have shown that milk protein crystals found in roaches can serve as a “fantastic” protein supplement.

The team of scientists, including those from the Institute for Stem Cell Biology and Regenerative Medicine (inStem) in Bengaluru, has recently unravelled the structure of milk proteins crystals in the guts of a roach species called Diploptera punctata, the only known viviparous cockroach (which gives birth to live young).

A single crystal is estimated to contain more than three times the energy of an equivalent mass of dairy (buffalo) milk, according to the study by inStem’s Ramaswamy group.

“The crystals are like a complete food — they have proteins, fats and sugars. If you look into the protein sequences, they have all the essential amino acids,” said Sanchari Banerjee, one of the main authors of the paper published in July in the journal from the International Union of Crystallography.

Now, armed with the gene sequences for these milk proteins, Ramaswamy and colleagues plan to use a yeast system to produce these crystals en masse.

“They’re very stable. They can be a fantastic protein supplement,” said Ramaswamy.

Furthermore, their crystalline nature offers a unique advantage. As the protein in the solution is used up, by being digested, the crystal releases protein at an equivalent rate.

“It’s time-released food,” explained Ramaswamy, adding “if you need food that is calorifically high, that is time released and food that is complete. This is it”.

Besides their utility as supplemental food, the scaffolding in the protein crystals exhibit characteristics that could be used to design nanoparticles for drug delivery.

The other scientists involved are affiliated to National Centre for Advancing Translational Sciences, National Institutes of Health in the US, Structural Biology Research Centre, High Energy Accelerator Research Organisation in Japan, Centre for Cellular and Molecular Platforms (C-CAMP) in India, Department of Cell and Systems Biology, University of Toronto in Canada, University of Iowa in the US and Experimental Division, Synchrotron SOLEIL in France.


Protein That Can Edit Other Proteins Without DNA Blueprint Discovered

In our cells, proteins are the tiny machines that do most of the work. And the instructions for making proteins — and for piecing together their building blocks, called amino acids — are laid out by DNA, then relayed through RNA. But now, researchers show for the first time that amino acids can be assembled by another protein — without genetic instructions. These surprising findings were published in Science this week.

If a cell is an automobile-making factory, then ribosomes are the machines on the protein assembly line that links together amino acids in an order specified by DNA and messenger RNA (mRNA), an intermediate template. If something goes awry and a ribosome stalls, the quality control team shows up to disassemble the ribosome, discard that bit of genetic blueprint, and recycle the partially-made protein.

Turns out, that assembly line can keep going even if it loses its genetic instructions, according to a large U.S. team led by University of Utah, University of California, San Francisco, and Stanford researchers. They discovered an unexpected mechanism of protein synthesis where a protein, and not the normal genetic blueprint, specifies which amino acids are added.

“In this case, we have a protein playing a role normally filled by mRNA,” UCSF’s Adam Frost says in a news release. “I love this story because it blurs the lines of what we thought proteins could do.”

Frost and colleagues found a never-before-seen role for one member of the quality control team: a protein named Rqc2, which helps recruit transfer RNA (tRNA) to sites of ribosomal breakdowns (tRNA is responsible for bringing amino acids to the protein assembly line). Before the incomplete protein gets recycled, Rqc2 prompts the stalled ribosomes to add two amino acids — alanine and threonine — over and over. And that’s because the Rqc2–ribosome complex binds tRNAs that carry those two specific amino acids. In the auto analogy, the assembly line keeps going despite having lost its instructions, picking up whatever it can and attaching it in no particular order: horn-wheel-wheel-horn-wheel-wheel-wheel-wheel-horn, for example.

Pictured above, Rqc2 (yellow) binds tRNAs (blue and teal), which add amino acids (bright sot in the middle) to a partially-made protein (green). The complex binds the ribosome (white). A truncated protein with a seemingly random sequence of alanines and threonines probably doesn’t work properly, and that tail could be a code that signals for the malformed protein to be destroyed.


Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community.