Category: 7. Science

Slow-motion earthquakes, as you might guess from the name, involve the release of pent-up geological energy over the course of days or weeks rather than minutes – and scientists have now recorded some as they were happening.

These quakes, also known as slow slip earthquakes or just slow earthquakes, are typically too gentle to cause immediate danger. However, they can help scientists predict full-speed earthquakes or tsunamis, which can of course be far more dangerous.

A team led by researchers from the University of Texas Institute for Geophysics (UTIG) tracked two separate slow slip events (SSEs) in real time – one in 2015 and another in 2020.

Special borehole sensors were positioned deep underwater, close to the Nankai Trough subduction zone off the coast of Japan. There, the Philippine Sea plate is pushing under the Eurasian plate. The researchers describe the activity of the slow quakes as being like a tectonic shock absorber.

“It’s like a ripple moving across the plate interface,” says hydrogeophysicist Josh Edgington, from UTIG.

Related: Earthquakes Today Could Be Echoes of Powerful Quakes Centuries Ago

The measurements confirm what scientists had previously thought about these slow-motion earthquakes, which were only recently discovered: that they can be significant in releasing (or building) stress around a faultline.

This subduction zone is part of the Pacific Ring of Fire, an extensive collection of volcanoes and faults surrounding the Pacific Ocean. It’s responsible for many of the largest earthquakes and tsunamis on record.

And the findings here, about the shock absorber effect, will be crucial in understanding when and where future earthquakes could hit. Other faults lack this kind of tectonic protection, including Cascadia off the western coast of North America.

“This is a place that we know has hosted magnitude 9 earthquakes and can spawn deadly tsunamis,” says geophysicist Demian Saffer, from UTIG. “Are there creaks and groans that indicate the release of accumulated strain, or is the fault near the trench deadly silent?”

“Cascadia is a clear top-priority area for the kind of high-precision monitoring approach that we’ve demonstrated is so valuable at Nankai.”

It’s only possible to measure these SSEs because of advances in sensor technology, meaning shakes of much lower strength – sometimes only shifting the ground a few millimeters at a time – can be detected.

Through their analysis, the researchers were able to determine that slow earthquakes may be related to high geologic fluid pressures, and that the upper part of the fault can release pressure independently of the rest of it.

All of this helps to inform models predicting earthquakes and tsunamis – with the potential to save thousands of lives. The last major Nankai Trough quake happened in 1946, with the loss of tens of thousands of properties and causing more than 1,300 deaths.

Predicting earthquakes isn’t an exact science, with a host of variables involved, but it’s something we’re getting better at. With each study and technological upgrade, seismologists are improving their models, and adding in data from slow earthquake activity could help greatly.

“The patterns of strain accumulation and release along the offshore reaches of subduction megathrusts are particularly important toward understanding hazards associated with shallow coseismic slip and tsunamigenesis,” write the researchers in their published paper.

The research has been published in Science.

KNOXVILLE, TN, July 08, 2025 /24-7PressRelease/ — Researchers explore how 6-PPD quinone (6-PPDQ), an environmental contaminant derived from tire antioxidant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), affects the citric acid cycle in C. elegans at environmentally relevant concentrations. The research reveals significant reduction in the citric acid cycle intermediates and key enzyme gene expressions by 6-PPDQ exposure, highlighting the its potential exposure risk on citric acid cycle metabolism.

6-PPDQ, has emerged as an environmental concern due to its widespread detection and toxic effects. In a study published in Environmental Chemistry and Ecotoxicology, researchers from Southeast University in China explored the effects of 6-PPDQ on the citric acid cycle and underlying mechanism in C. elegans. The citric acid cycle, a crucial metabolic pathway occurring in the mitochondria, plays a central role in cellular metabolism by linking carbohydrate, fat, and amino acid metabolisms. It provides intermediates for the synthesis of amino acids, fatty acids, and glycogen, which are essential for sustaining life activities.

The study reveals how 6-PPDQ at environmentally relevant concentrations (0.1–10 μg/L) disrupted the citric acid cycle by reducing intermediate metabolites, including citric acid, α-ketoglutarate, succinate, fumarate, malate, and oxaloacetate. Additionally, the reduction of these intermediate metabolites was due to the inhibition of relevant key enzyme gene expressions. Exposure to 6-PPDQ suppressed genes encoding citrate synthase (cts-1), isocitrate dehydrogenase 2 (idh-2), and α-ketoglutarate dehydrogenase complex (dlst-1, dld-1). As explained by the researchers, “exposure to 6-PPDQ significantly impacts the citric acid cycle in C. elegans, which is crucial for understanding the potential risks of this contaminant to both environmental and human health.”

The researchers also observed that 6-PPDQ exposure decreased acetyl CoA and pyruvate contents, which are important for the control of citric acid cycle. Acetyl CoA generated from pyruvate is a key substrate for the cycle. The study found that among the genes encoding components of the pyruvate dehydrogenase complex, which controls acetyl CoA synthesis, only dlat-1 and dld-1 expressions were decreased by 6-PPDQ. The expressions of genes pyk-1 and pyk-2 associated with pyruvate generation were also reduced. RNA interference (RNAi) of these genes further exacerbated the cycle’s disruption, highlighting the crucial contribution of these alterations to 6-PPDQ-induced toxicity.

The study also demonstrated that the disruption in citric acid cycle and reduction in acetyl CoA and pyruvate contents contributed to mitochondrial dysfunction, as indicated by increased oxygen consumption rates and decreased ATP content in 6-PPDQ exposed nematodes. Furthermore, the researchers investigated the protective effects of sodium pyruvate treatment, finding that it could suppress toxic effects of 6-PPDQ. “Our results suggest that sodium pyruvate treatment may be a promising approach to against 6-PPDQ toxicity,” the researchers concluded.

This study provides valuable insights into the mechanisms by which 6-PPDQ disrupts metabolic process of citric acid cycle and highlights the potential risks of this contaminant. The findings underscore the importance of further research to fully understand the implications of 6-PPDQ exposure for both environmental and human health.

References

DOI

10.1016/j.enceco.2025.05.022

Original Source URL

https://doi.org/10.1016/j.enceco.2025.05.022

Journal

Environmental Chemistry and Ecotoxicology

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Scientists have identified a new type of protein in bacteria that could change our understanding of how these organisms interact with their environments.

A new study, published in Nature Communications, focuses on a protein called PopA, found in the bacterial predator Bdellovibrio bacteriovorus. The protein forms a unique fivefold structure, unlike the usual single or three-part structures seen in similar proteins.

Supported by the Wellcome Trust, BBSRC, ERC, MRC, and EPSRC an international research team, led by University of Birmingham scientists, used advanced imaging techniques to reveal that PopA has a bowl-like shape that can trap parts of the bacterial membrane inside it.

When PopA – an outer membrane protein (OMP) – is introduced into E. coli bacteria, it causes damage to their membranes. This suggests that PopA might play a role in how Bdellovibrio attacks and consumes other bacteria, whilst its ability to trap lipids (fats) suggests a new way bacteria might interact with their surroundings.

Structural analysis and AI-driven searches showed that PopA homologues – found across diverse bacterial species – form tetramers, hexamers, and even nonamers, all sharing the signature lipid‑trapping features. This suggests a widespread, previously unrecognised ‘superfamily’ of proteins.

Our discovery is significant because it challenges what scientists thought they knew about bacterial proteins. The unique structure and function of PopA suggest that bacteria have more complex ways of interacting with their environments than previously understood.

This could open new possibilities for understanding how bacteria function and interact with their environments – leading to new ways to target harmful bacteria with important implications for medicine and biotechnology.”

Professor Andrew Lovering, Lead Author, University of Birmingham

The study also identified another new family of proteins that form ring-like structures, further expanding our knowledge of bacterial proteins and suggesting that the mechanism to combine into rings might be more common than previously thought.

Using a combination of X‑ray crystallography, cryo-electron microscopy, and molecular dynamics, the team demonstrated that PopA, previously known as Bd0427, forms a central lipid-trapping cavity which is unusual given that the textbook model of membrane protein formation is centred on excluding lipids.

OMPs perform a wide range of functions including signalling, host cell adhesion, catalysis of crucial reactions, and transport of solutes/nutrients into and out of organelles within the human body. Understanding the natural variability of OMPs may have benefits ranging from antibacterial development to synthetic biology.

CAGLIARI, Sardinia, Italy, 8 July 2025 – In a comprehensive Genomic Press Interview published today in Genomic Psychiatry, Dr. Mirko Manchia opens up about his transformative journey from a small Sardinian city to becoming a leading voice in psychiatric pharmacogenomics, revealing how personal family experiences with mental illness sparked a lifelong quest to understand why psychiatric medications work brilliantly for some patients while failing others.

The Associate Professor of Psychiatry at the University of Cagliari has spent decades unraveling one of psychiatry’s most perplexing puzzles: why does lithium, psychiatry’s oldest mood stabilizer, transform some bipolar patients’ lives while leaving others searching for alternatives?

From Personal Experience to Scientific Breakthrough

Growing up in Sassari with no medical background in his family, Dr. Manchia’s path into neuroscience began with what he describes as “profound familial events” during adolescence that connected him deeply with mental health. This personal connection would later fuel groundbreaking research that culminated in a landmark publication in The Lancet, identifying genome-wide significant associations for lithium response in bipolar patients.

“I saw patients who had severe illness trajectories and who had remained well after several years of treatment with mood stabilizers, especially lithium, while others experienced continuous recurrences with dire consequences on their lives,” Dr. Manchia reflects in the interview. This observation became the cornerstone of his research philosophy.

Building International Collaborations

As a co-investigator and founding member of the International Consortium on Lithium Genetics (ConLiGen), Dr. Manchia has helped coordinate one of psychiatry’s most ambitious pharmacogenetic efforts. His meticulous phenotypic analysis of patient samples has been instrumental in identifying genetic markers that could predict treatment response before patients endure months of trial-and-error medication adjustments.

The impact extends far beyond lithium. With 230 peer-reviewed publications spanning molecular genetics and clinical psychiatry, Dr. Manchia has established himself as a bridge between laboratory discoveries and real-world patient care. His dual appointments at Cagliari and Dalhousie University in Canada reflect this international reach.

Precision Medicine Takes Center Stage

Currently serving as chair of the European College of Neuropsychopharmacology (ECNP) Bipolar Disorders Network, Dr. Manchia envisions a future where genetic testing becomes routine in psychiatric care. “We are at a point in psychiatric genetics where clinical utility is emerging,” he states. His current focus includes developing healthcare pathways that integrate pharmacogenetic testing for treatment-resistant depression and implementing AI-based predictive tools.

What makes this vision particularly compelling is its practical application. Rather than pursuing abstract genetic associations, Dr. Manchia’s work centers on questions every psychiatrist faces: Which patient will respond to this medication? How can we minimize the devastating trial-and-error period that often characterizes psychiatric treatment? Can we predict and prevent treatment resistance before it develops?

Addressing Research Disparities

The interview also highlights a critical challenge facing psychiatric research: chronic underfunding compared to other medical specialties. Dr. Manchia advocates for increased investment, noting that oncology’s transformation followed massive research funding. “This could also be achieved in psychiatry, but we need to act in a harmonized way, involving all stakeholders, particularly patient and family associations,” he emphasizes.

His approach to this challenge reflects the same patient-centered philosophy that drives his research. By involving patient organizations in research development and dissemination, Dr. Manchia believes the field can build the public support necessary for sustained funding increases.

Looking Ahead: Digital Integration and Beyond

The interview reveals Dr. Manchia’s vision for psychiatry’s future, where digital monitoring, psychometric assessments, genomics, and brain imaging converge into comprehensive predictive models. Within 20 years, he predicts, these integrated approaches will fundamentally transform how mental health is managed and delivered.

Yet despite these technological advances, Dr. Manchia’s motivations remain deeply human. When asked about his greatest passion beyond science, he mentions Roman history, classical music, and playing guitar – reminders that even cutting-edge researchers need balance and perspective.

Dr. Mirko Manchia’s Genomic Press interview is part of a larger series called Innovators & Ideas that highlights the people behind today’s most influential scientific breakthroughs. Each interview in the series offers a blend of cutting-edge research and personal reflections, providing readers with a comprehensive view of the scientists shaping the future. By combining a focus on professional achievements with personal insights, this interview style invites a richer narrative that both engages and educates readers. This format provides an ideal starting point for profiles that explore the scientist’s impact on the field, while also touching on broader human themes. More information on the research leaders and rising stars featured in our Innovators & Ideas – Genomic Press Interview series can be found in our publications website: https://genomicpress.kglmeridian.com/.

The Genomic Press Interview in Genomic Psychiatry titled “Mirko Manchia: Exploring the biological landscape of psychiatric disorders to innovate clinical management with precision medicine approaches,” is freely available via Open Access on 8 July 2025 in Genomic Psychiatry at the following hyperlink: https://doi.org/10.61373/gp025k.0071.

About Genomic Psychiatry: Genomic Psychiatry: Advancing Science from Genes to Society (ISSN: 2997-2388, online and 2997-254X, print) represents a paradigm shift in genetics journals by interweaving advances in genomics and genetics with progress in all other areas of contemporary psychiatry. Genomic Psychiatry publishes high-quality medical research articles of the highest quality from any area within the continuum that goes from genes and molecules to neuroscience, clinical psychiatry, and public health.

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Landmark research on MCL-1, a critical protein that is an attractive target for cancer drug development, helps explain why some promising cancer treatments are causing serious side effects, and offers a roadmap for designing safer, more targeted therapies. 

The WEHI-led discovery, published in Science, has uncovered a critical new role for MCL-1, revealing it not only prevents cell death but also provides cells with the energy they need to function. 

The findings reshape our understanding of how cells survive and thrive, with implications for both cancer treatment and developmental biology. 

At a glance 

• Landmark research shows the protein MCL-1, in addition to its well-understood role in preventing cell death, plays a second essential role in helping cells function by supporting energy production. 
• Drugs targeting MCL-1 have shown great promise as a future cancer treatment, but have been shown to harm healthy tissues, especially in organs with high energy demand like the heart and liver. 
• The findings published in Science pave the way for safer, more targeted cancer therapies targeting MCL-1. 

First author Dr. Kerstin Brinkmann said that while previous research in cell cultures had hinted at the metabolic role of MCL-1 in providing energy to cells, it was unclear whether this mattered in living organisms. 

This is the first time MCL-1’s metabolic function has been shown to be critical in a living organism.

It’s a fundamental shift in how we understand what this protein does. 

The findings open up a completely new way of thinking about the intersection between programmed cell death and metabolism – something that’s been speculated on for years but never been shown in a living organism until now.” 

Dr. Kerstin Brinkmann, WEHI researcher

Cancer drug target 

The research strengthens the potential of MCL-1 as a cancer drug target, which is currently the subject of clinical trials all over the world. 

While drug compounds targeting MCL-1 that have been developed to date are considered extremely effective at combating cancer, they have unfortunately also caused significant side effects in early clinical trials, particularly in the heart. 

Co-senior researcher Professor Andreas Strasser said the findings could help resolve the safety issues of drugs targeting MCL-1 that have hindered these promising treatments. 

“If we can direct MCL-1 inhibitors preferentially to tumour cells and away from the cells of the heart and other healthy tissues, we may be able to selectively kill cancer cells while sparing healthy tissues,” Prof Strasser, a WEHI laboratory head, said. 

The study also lays the groundwork for better combination therapies. By understanding the distinct pathways the protein influences, researchers can design smarter dosing strategies and pair MCL-1 inhibitors with other treatments to reduce toxicity. 

“This work exemplifies the power of discovery science,” said co-senior researcher Professor Marco Herold, CEO of the Olivia Newton-John Cancer Research Institute (ONJCRI). 

“The sophisticated preclinical models we developed allow us to interrogate the precise function of MCL-1, and to address fundamental biological questions that have direct relevance to human disease.” 

Protein link to rare, fatal diseases 

MCL-1’s role in energy production could help explain fatal metabolic diseases in infants, such as mitochondrial disorders. These rare conditions, often caused by mutations in genes that stop cells from generating enough energy, can be lethal in early life. 

The study suggests MCL-1 may play a previously unrecognised role in these diseases, offering a potential new target for future therapies. 

Another key outcome of the study is the creation of a system that allows researchers to compare the functions of pro-survival proteins like MCL-1, BCL-XL and BCL-2. 

These new tools will help identify which roles are shared and which are unique – knowledge that could inform future drug development across multiple targets. 

A collaborative discovery 

The project was made possible by WEHI’s collaborative research environment, bringing together experts in cancer biology, metabolism, developmental biology and gene editing. 

Co-senior authors Prof Herold (from the ONJCRI), Associate Professor Tim Thomas and Professor Anne Voss played key roles in the study. 

“This kind of discovery only happens when you have the right mix of people and expertise,” said Prof Strasser. 

“It’s a powerful example of how fundamental science drives future medical breakthroughs. 

“This came from a simple biological question – not a drug development project. It shows why we need to support curiosity-driven science. That’s where the big insights come from.” 

A new study has revealed a startling link between climate change and increased volcanic activity, warning that the rapid melting of glaciers and ice caps, especially in regions like West Antarctica, could trigger hundreds of explosive volcanic eruptions worldwide. The research, based on geological data from Chile’s Andes Mountains, demonstrates how retreating ice removes pressure on underground magma chambers, making eruptions more likely and more violent. Scientists believe this mechanism, already observed in Iceland, could apply across several glaciated regions of the world. The biggest concern lies beneath Antarctica’s thick ice, where at least 100 volcanoes remain buried. As global temperatures rise, this hidden volcanic threat could become a dangerous feedback loop that further accelerates climate change.

From ice to fire: The chain reaction beneath our feet

According to the study presented at the Goldschmidt Geochemistry Conference in Prague, glaciers suppress volcanic activity by exerting immense pressure on magma chambers beneath Earth’s surface. As the ice melts due to global heating, this pressure lifts, allowing gases in magma to expand and erupt explosively. Researchers found that after the last Ice Age, regions like Chile experienced a surge in volcanism, offering a chilling preview of what could happen as modern glaciers disappear.

Case study from Chile’s Andes

Lead researcher Pablo Moreno-Yaeger and his team studied Mocho-Choshuenco, a volcano in Chile, using radioisotope dating of volcanic rocks. Their findings show that thick ice cover between 26,000 and 18,000 years ago suppressed eruptions. Once the ice melted around 13,000 years ago, the volcano erupted more frequently and more violently. The magma became more viscous due to prolonged underground buildup, increasing the explosiveness when finally released.

The growing risk in Antarctica

The West Antarctic Ice Sheet, already under threat from rising temperatures, covers at least 100 known volcanoes. Scientists warn that the loss of this ice could unleash significant volcanic activity in the region. While eruptions can temporarily cool the planet by releasing sunlight-blocking particles, sustained volcanic activity would inject carbon dioxide and methane into the atmosphere, intensifying global warming.

Global implications beyond Antarctica

Though much of the focus is on Antarctica, other glaciated regions such as North America, New Zealand, and Russia could also be at risk. The findings urge scientists and policymakers to monitor glacial regions more closely and prepare for possible climate volcano feedback loops. More research is now considered “critically important” to understand how warming temperatures may interact with Earth’s geologic systems.

A call for urgent study

Despite the potentially massive impact, volcanism remains under-studied in climate change models. Researchers say it’s vital to factor in geological responses like eruptions into our understanding of climate risks. As more glaciers retreat and expose ancient volcanoes, the Earth’s response may not be slow or quiet, but loud, explosive, and globally disruptive.

In vertebrates, sleep changes the way the brain responds to stimuli, specifically disrupting neural responses to unexpected sounds. Now, researchers have found that Drosophila brains, too, selectively process sensory information during sleep.

The work, by Bruno van Swinderen, professor of behavior and cognition at the Queensland Brain Institute, and postdoctoral research fellow Matthew Van De Poll, was published in the June issue of the Journal of Experimental Biology.

It’s known that sleeping fruit flies sense the external world—a 2021 study found that the smell of food wakes them up. And in previous work, van Swinderen and his colleagues recorded local field potentials from 16 sites across one hemisphere of the brain of sleeping Drosophila—all the way from the optic lobes near the eyes to the central complex. In the new study, the researchers wanted to test neural response to surprising stimuli in sleeping flies.

They used the same multi-channel probes to record evoked potentials in response to visual stimuli in awake and sleeping Drosophila. The stimuli combined green and blue flashes of light—one sequence favored green and the other blue. The researchers found that both color stimuli evoked similar potentials in the optic lobes of awake flies, but when the flies were asleep, a surprising color flash—blue amidst a series of green, for instance—generated a lower response in the central brain region. And responses to surprising stimuli were the lowest in the deepest stages of fly sleep, when Drosophila rhythmically extend their proboscis to clear waste from their brain.

The results suggest that the Drosophila central brain region is sensitive to both the color of light flashes and the probability of the stimulus. During sleep, something happens between the optic lobes and the central brain region to filter out low-probability stimuli, van Swinderen says.

Giorgio Gilestro, reader in systems neurobiology at Imperial College London, who was not involved in the study, says that it “is an important work because it shows clear electrophysiological correlates of sleep that create a nice link between the invertebrate and vertebrate literature.” Indeed, previous work suggests that humans also exhibit smaller responses to low-probability stimuli during sleep, but the mechanism for these selective responses in both vertebrates and invertebrates is unclear. Gilestro says that in vertebrates, “we don’t know exactly what are the circuits regulating this, beside the fact that it must happen in the thalamus.”

Regardless, van Swinderen says it’s clear that both vertebrate and invertebrate brains have mechanisms that modulate responses to surprising and predictable stimuli when animals sleep. “There are predictions being made in the fly brain about what happens next, and when these predictions match the outside world, you have behavior; you have memory; you have the kind of things that normally happen in an awake animal,” he says. “And I think in the case of sleep, these predictions, in a way, are not being met or turned off.”

B

efore van Swinderen’s new study, sleep research in Drosophila mainly focused on fly behavior, says Krishna Melnattur, assistant professor of psychology and biology at Ashoka University, who was not involved in the study. And without unambiguous neural correlates of sleep in flies, he says, drawing parallels between sleep in Drosophila and vertebrates has been challenging.

The work by van Swinderen’s group has helped fill that hole, Gilestro says.

But beyond the parallels with vertebrate sleep, he says, it is hard to draw many conclusions about how the sensory disconnect might be orchestrated during sleep, or what its role might be. This is because flashing lights don’t carry any particular meaning for a fly. “It’s a good step, but I do not attribute too much ecological relevance to it,” he says.

Van Swinderen says he hopes to investigate relevance next, and that he has been thinking about the way the awake brain also filters sensory input. About four years ago, while riding a ferry in Brisbane, Australia, surrounded by other boats passing by, passengers talking, and the sounds of kookaburras and cockatoos in the trees, he realized he was neither overstimulated nor actively tuning it all out.

The brain, he says, “has to be able to manage that level of prediction versus surprise and keep it right in that middle ground.”

He proposed in a 2021 review that sleep somehow holds the key to how the brain does this. He next plans to manipulate specific stages of sleep using transgenic flies and study whether they optimize predictions during sleep and waking states.

“This would be something extremely ancient. In humans, it just manifests as curating consciousness, but it would have been there in any animal that basically needs to optimize how it pays attention to the world,” he says.

To build proteins, cells rely on a molecule called transfer RNA, or tRNA. tRNAs act like protein-building couriers, where they read the genetic instructions from messenger RNA, mRNA, and deliver the right amino acids to ribosomes, the cell’s protein-making factories. But before tRNAs can do their work, they first need to be trimmed and shaped properly.

Now, researchers from Kyushu University have revealed that the smallest known protein-based tRNA-processing enzyme, called HARP, forms a star-shaped complex of 12 protein molecules, making it capable of cutting both the 5′ and 3′ ends of tRNA. The team hopes that their findings will have a broad impact on synthetic biology and biotechnology research, and aid in the designing of artificial enzymes and RNA processing tools. Their findings were published in the journal Nature Communications.

In any biological system, most proteins that are made in the cell need to undergo processing for them to fully work. In the case of tRNA, one of those processes is the cutting of the straggling ends of the RNA that make up the molecule. Depending on the direction, these are called 5-prime or 3-prime ends, denoted as 5′ and 3′, respectively.

One key enzyme responsible for cutting the extra segment at the 5′ end of the tRNA is RNase P. Found in almost all life forms, this enzyme exists in two broad forms: one that is mostly made of RNA and another that is entirely protein-based. The RNA-based version usually forms a large, complex structure with several proteins and has been well studied over the past 40 years.

On the other hand, protein-only RNase P enzymes are more streamlined. These come in two main types: PRORP, which is found in higher organisms like plants and animals, and HARP, which is found in certain bacteria and archaea. HARP-short for Homologs of Aquifex RNase P36-is known for its small size and unique six-pointed, star-like structure. But how it performs such a complex task-or why it forms such a distinctive shape-remained unclear.

“To investigate and visualize HARP bound to pre-tRNA and uncover how it processes the molecule, we used cryogenic electron microscopy (cryo-EM) single-particle analysis,” explains Professor Yoshimitsu Kakuta from Kyushu University’s Faculty of Agriculture, who led the study.

The researchers found that the overall structure of the enzyme with the pre-tRNAs had a radial structure with pre-tRNA molecules alternately bound to five binding sites on the enzyme. Cryo-EM analysis showed that the 12-subunit HARP enzyme acts like a “molecular ruler,” measuring the distance from the 5′ end to the “elbow” of the pre-tRNA to precisely identify the cleavage site. Remarkably, this mechanism was also observed in other types of RNase P enzymes, indicating a case of convergent evolution across different organisms.

Our structural analysis shed light on how HARP processes the 5′ leader sequence and revealed that the functional 12-subunit HARP complex binds only five pre-tRNA molecules, not ten as previously predicted. This means that 7 of the enzyme’s 12 active sites remain unoccupied.”

Assistant Professor Takamasa Teramoto, first author of the study

When the team conducted cleavage assays to understand the functionality of these vacant sites, they found a second cleavage product that corresponded to the 3′ end of the pre-tRNA. This was a new finding. It suggests that HARPs first trim the extra nucleotides at the 5′ end and then use the remaining empty active sites to carry out the cleavage at the 3′ end.

“The oligomerization of the small protein HARP confers it with bifunctionality in pre-tRNA processing. Our findings illustrate an evolutionary strategy by which organisms with compact genomes can acquire multifunctionality,” concludes Kakuta.

Uncovering such evolutionary strategies where limited structural elements are arranged flexibly to gain new functions could assist in the development of future tools in synthetic biology and biotechnology.