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Researchers have cracked the cellular code on protein folding, offering hope for new therapeutic avenues for many diseases

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Researchers have cracked the cellular code on protein folding, offering hope for new therapeutic avenues for many diseases


While we often think of diseases as caused by foreign bodies — bacteria or viruses — there are hundreds of diseases affecting humans that result from errors in cellular production of its proteins. A team of researchers led by the University of Massachusetts Amherst recently leveraged the power of cutting-edge technology, including an innovative technique called glycoproteomics, to unlock the carbohydrate-based code that governs how certain classes of proteins form themselves into the complex shapes necessary to keep us healthy.

The research, published in the journal Molecular Cell, explores members of a family of proteins called serpins, which are implicated in a number of diseases. The research is the first to investigate how the location and composition of carbohydrates attached to the serpins ensure that they fold correctly. Serious diseases — ranging from emphysema and cystic fibrosis to Alzheimer’s disease — can result when the cellular oversight of protein folding goes awry. Identifying the glyco-code responsible for high-fidelity folding and quality control could be a promising way for drug therapies to target many diseases.

Scientists once thought that the single code governing life was DNA, and that everything was governed by how DNA’s four building blocks — A, C, G and T — combined and recombined. But in recent decades, it has become clear that there are other codes at work, and especially in building the intricately folded, secreted proteins that are created in the human cell’s protein factory, the endoplasmic reticulum (ER), a membrane-enclosed compartment where protein folding begins. Approximately 7,000 different proteins — one third of all the proteins in the human body — mature in the ER. The secreted proteins — collectively known as the “secretome” — are responsible for everything from our body’s enzymes to its immune and digestive systems and must be formed correctly for the human body to function normally.

Special molecules called “chaperones,” help fold the protein into its final shape. They also help to identify proteins that haven’t folded quite correctly, lending them additional help in refolding, or, if they’re hopelessly misfolded, targeting them for destruction before they cause damage. However, the chaperone system itself, which comprises a part of the cell’s quality control department, sometimes fails, and when it does, the results can be catastrophic for our health.

The discovery of the carbohydrate-based chaperone system in the ER was due to the pioneering work that Daniel Hebert, professor of biochemistry and molecular biology at UMass Amherst and one of the paper’s senior authors, initiated as a postdoctoral fellow in the 1990s. “The tools we have now, including glycoproteomics and mass spectrometry at UMass Amherst’s Institute for Applied Life Sciences, are allowing us to answer questions that have remained open for over 25 years,” says Hebert. “The lead author of this new paper, Kevin Guay, is doing things I could only dream of when I first started.”

Among the most pressing of these unanswered questions is: how do chaperones know when 7,000 different origami-like proteins are correctly folded?

We know now that the answer involves an “ER gatekeeper” enzyme known as UGGT, and a host of carbohydrate tags, called N-glycans, which are linked to specific sites in the protein’s amino acid sequence.

Guay, who is completing his Ph.D. in the molecular cellular biology program at UMass Amherst, focused on two specific mammalian proteins, known as alpha-1 antitrypsin and antithrombin. Using CRISPR-edited cells, he and his co-authors modified the ER chaperone network to determine how the presence and location of N-glycans affected protein folding. They watched as the disease variants were recognized by the ER gatekeeper UGGT and, in order to peer more closely, developed a number of innovative glycoproteomics techniques using mass spectrometry to understand what happens to the glycans that stud the surface of the proteins.

What they discovered is that the enzyme UGGT “tags” misfolded proteins with sugars placed in specific positions. It’s a sort of code that the chaperones can then read to determine exactly where the folding process went wrong and how to fix it.

“This is the first time that we’ve been able to see where UGGT puts sugars on proteins made in human cells for quality control,” says Guay. “We now have a platform for extending our understanding of how sugar tags can send proteins for further quality control steps and our work suggests that UGGT is a promising avenue for targeted drug therapy research.”

“What’s so exciting about this research,” says Lila Gierasch, distinguished professor of biochemistry and molecular biology at UMass Amherst and one of the paper’s co-authors, “is the discovery that glycans act as a code for protein folding in the ER. The discovery of the role that UGGT plays opens the door to future advancement in understanding and eventually treating the hundreds of diseases that result from misfolded proteins.”



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Moon orbiting ‘dinky’ asteroid is actually two tiny moons stuck together

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Moon orbiting ‘dinky’ asteroid is actually two tiny moons stuck together


When NASA’s Lucy spacecraft flew past its first official target Dinkinesh in November 2023, researchers discovered that the asteroid — known as “Dinky” — was not alone in space. A satellite asteroid, which the team named “Selam,” was orbiting Dinky. As Lucy sent more data back to Earth, the researchers discovered something surprising: Selam was not just one moon, it was a contact binary — or two moons melded together.

The Lucy team, which includes University of Maryland Professor of Astronomy and Geology Jessica Sunshine, detailed the unexpected finding in a paper published in the journal Nature on May 29, 2024. The researchers noted that the unusual arrangement challenges existing theories about how asteroids and other celestial bodies formed over time and provides additional insight into the internal structure, dynamics and evolutionary history of both Dinky and Selam.

“There’s a lot more complexity in these small bodies than we originally thought,” said Sunshine, a co-author of the paper. “With the additional observations taken by the spacecraft, we were able to better analyze features such as Dinkinesh’s rotation speed and Selam’s orbit pattern. We also have a better understanding of what materials they’re possibly made of, bringing us a step closer to learning just how terrestrial bodies are created.”

Images taken by the Lucy spacecraft revealed a trough on Dinkinesh where about a quarter of the asteroid broke off from its main body, a ridge that formed after the asteroid’s structural failure and the contact binary now known as Selam (which was named after the child counterpart of the Lucy hominin fossil discovered in 1974). The team theorized that Dinky’s fast spinning motion — boosted by the uneven reflection of sunlight off the asteroid’s surface — caused it to shed and eject rocky debris into orbit. Some of the debris could have aggregated to form Selam, while another portion of the fragments rained back down on Dinky as boulders and created the ridges photographed by the Lucy spacecraft.

“One of the things that’s critical to understanding how planets like Earth got here is understanding how objects behave when they hit each other, and to understand that we need to understand their strength,” said lead scientist Hal Levison of Southwest Research Institute, Boulder, Colorado, principal investigator for the Lucy mission. “Basically, the planets formed when [smaller objects like asteroids] orbiting the Sun ran into each other. Whether objects break apart when they hit or stick together has a lot to do with their strength and internal structure.”

The team deduced that Dinky likely had some internal strength, which allowed it to maintain most of its form.

Just how Dinky’s unusual dual moons formed remains a mystery, but Sunshine said that the team’s findings open the door to comparative studies with similar celestial bodies.

“I’m personally very excited to compare the Didymos binary system with this one, especially as they appear to share many similarities such as size, general shape and possibly composition despite being in totally different parts of the solar system,” explained Sunshine, who was also on NASA’s DART research team and helped detail the DART spacecraft’s successful deflection of Didymos’ small moon called Dimorphos.

“The Didymos binary system is located in a near-Earth environment while the Dinkinesh system is located much farther away from Earth in the main asteroid belt,” she added. “They have very different features but we think they may have undergone similar processes to become what we know of them today.”

Dinkinesh and its satellite are the first two of 11 asteroids that Lucy plans to explore over its 12-year journey. After skimming the inner edge of the main asteroid belt, Lucy heads back toward Earth for a gravity assist in December 2024. That close flyby will propel the spacecraft back through the main asteroid belt, where it will observe asteroid Donaldjohanson in April 2025, and then move on to observe the Trojan asteroids in 2027.

“Our ultimate goal is to understand the formation of celestial bodies,” Sunshine said. “How do planets form? How was Earth formed? We know that big planets are formed by smaller bodies, so studying these little asteroids lets us see how materials behave and interact on a smaller scale. With Dinky and the other asteroids we’re flying by, we’re laying the groundwork for understanding how planets are made.”



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Orchids support seedlings through ‘parental nurture’ via shared underground fungal networks

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Orchids support seedlings through ‘parental nurture’ via shared underground fungal networks


The Common Spotted Orchid (Dactylorhiza fuchsii) is found all over the UK. These orchids produce tiny seeds that can be carried anywhere by the wind, yet they often appear in clumps with small seedlings growing near mature plants. This phenomenon has puzzled ecologists since Darwin’s time, with the exact reason remaining a mystery.

A new study, led by researchers from the University of Sheffield in collaboration with The University of Manchester, provides the first evidence that early stage orchid seedlings germinate and thrive near to adult plants due to a kind of parental nurture using underground fungal networks.

Scientists investigated the idea that fungal networks, known as mycorrhizal networks, act as a direct pathway for established orchid plants to share recently produced sugars with developing seedlings.

Professor Katie Field, co-author of the study and Professor of Plant-Soil Processes at the University of Sheffield’s School of Biosciences, said: “Our results support the idea that some orchids engage in a form of ‘parental nurture’ with their seedlings. By supplying early stage seedlings with essential nutrients via shared fungal connections, the parent orchids give the seedlings an advantage over neighbouring plants that are competing for the same resources.

“This finding is exciting because why these orchids are often found in clumps, despite their seeds being wind dispersed, has been a puzzle for hundreds of years.”

The study focused on the Common Spotted Orchid and its fungal partner, Ceratobasidium cornigerum. Researchers created a system where mature, green orchids were connected to developing, chlorophyll-free seedlings through a fungal network grown on agar.

The mature plants were then exposed to a special form of carbon dioxide that could be tracked within the system.

Here’s how it worked:

  • Green orchid plants were connected to developing seedlings through the fungal network.
  • The green plants were then exposed to a special form of carbon dioxide that could be tracked within the system.
  • After a period of time, the researchers analysed both the seedlings and the fungal network to see where the labelled carbon ended up.

The results were clear, the seedlings were accumulating the labelled carbon, indicating they were being supported by the adult plants. By tracking the movement of carbon, the study showed that the mature orchids were indeed sharing their recently produced sugars with the seedlings through the fungal network.

Sir David Read, Emeritus Professor of Plant Sciences from the University of Sheffield and lead author of the study, said: “Whereas the seeds of most plants, for example legumes (peas, beans) and grasses (rice, corn, wheat) are fully provisioned with food reserves by their parent plants, the so-called dust seeds of orchids receive insufficient reserves from the parents to develop on their own.

“They are instead produced in their millions by each individual parent orchid plant from which they are dispersed, by wind, to the surrounding environment. Even Charles Darwin was puzzled by this strategy, suggesting that while it should enable the seeds of an individual orchid plant to be so widely distributed that within a few years it could colonise the whole world. He observed that their failure to do so ‘could not be understood at this time’.

“What is now revealed is that the belowground development of these essentially reserve-free seeds can be supported by photosynthetically produced sugars that are transported to them from mature plants growing above ground through a shared mycelium of symbiotic fungi.”

Results of the study, published in New Phytologist, show the amount of carbon transferred seemed to depend on the environment. When the fungus had access to a richer food source (oatmeal agar), less carbon was transferred to the seedling. This suggests that the strength of the demand from the seedlings may influence the flow of nutrients through the network.

This research has important implications for understanding orchid ecology and conservation efforts. By recognising the importance of fungal connections, scientists can develop better strategies for protecting these unique and often threatened plants.

Next steps are to research this theory in the natural habitat that the orchids are found in and to look at whether this applies to other species.



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Bird flu: Diverse range of vaccines platforms ‘crucial’ for enhancing human pandemic preparedness

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Bird flu: Diverse range of vaccines platforms ‘crucial’ for enhancing human pandemic preparedness


Vaccination remains the most effective strategy for avian influenza prevention and control in humans, despite varying vaccine efficacy across strains.

That’s according to the authors of a new review which delves into existing research into bird flu vaccines for humans.

Published in the peer-reviewed journal Human Vaccines & Immunotherapeutics, the results of the paper are particularly timely following news last week (Wednesday 22nd May) that the bird flu strain H5N1 had once again, for a second time, jumped from cattle in America to a human — prompting fears of subsequent human-to-human infection, with possible critical consequences.

Instances of the avian influenza were first recognized in US cattle in March. Since then, this strain has mainly spread from cow-to-cow and scientists have discovered very high levels of virus in raw milk (pasteurized milk is safe, having shown viral RNA but not infectious virus). To-date two people, however, are known to have contracted the bird flu virus. Both patients — US farmers — only reported eye symptoms and with treatment they made a full recovery.

Following tests on the first human instance, it was seen that the strain had mutated to be better adapted to mammalian cells, but as long as that human didn’t pass it onto another person it likely stopped the spread at that point. With the second case, the CDC has released a statement to say it has been monitoring influenza surveillance systems intently, especially in impacted states. “There has been no sign of unusual influenza activity in people, including in syndromic surveillance,” they report.

The concern now, though, is that if H5N1 continues to be given the environment in which to mutate (such as in close quarter cattle farms) — and this continues long enough — it has the potential to find a combination that will easily spread to humans.

The results of this new research, carried out by a team at the University of Georgia, USA, suggests vaccines still remain our “primary defense” against potential spread of avian influenzas such as the H5N1 and others assessed.

“The H5N1, H7N9, and H9N2 subtypes of avian influenza virus pose a dual threat, not only causing significant economic losses to the global poultry industry but also presenting a pressing public health concern due to documented spillover events and human cases,” explains lead author Flavio Cargnin Faccin, who alongside his mentor Dr. Daniel Perez of the University of Georgia, USA, analyzed the current landscape of research into human vaccines for these bird flus.

“This deep delve into the landscape of avian influenza vaccines for humans shows vaccination remains the primary defense against the spread of these viruses.”

The team examined studies of vaccines tested in mice, ferrets, non-human primates, and clinical trials of bird flu vaccines in humans, and assessed both established platforms and promising new directions.

The review carried out suggests inactivated vaccines are a safe and affordable option that primarily activate humoral immunity — the part of our immune system that produces antibodies.

Live attenuated influenza vaccines (LAIVs) are known to induce a wider immune response than inactivated vaccines, activating not only antibody production but also mucosal and cellular defenses. In this review, the authors suggest this broader response may offer greater protection, though, the authors suggest further research is needed to fully understand and harness its potential benefits for both human and agricultural applications.

The review also examined alternatives, such as virus-like particle (VLP) vaccines and messenger RNA (mRNA) vaccines, that have emerged more recently. Although VLP vaccines for bird flu have limited clinical trial data in humans, results from studies in mice and ferrets showed promise, the authors found. mRNA vaccines against H5N1 and H7N9 bird flu subtypes also generated a rapid and strong immune response in mice and ferrets, and, while data in humans is scarce, results from a phase 1 study of an H7N9 mRNA vaccine in healthy humans were “encouraging.”

Overall, the team suggests “exploring and employing a diverse range of vaccine platforms,” will be “crucial for enhancing pandemic preparedness and mitigating the threat of avian influenza viruses.”



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