Hexbyte Glen Cove ‘Like a magic trick,’ certain proteins pass through cell walls

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The researchers noticed that some peptides cross membranes by pushing against them. The peptides deformed the membrane into small circular buds. The buds then detach as small bubbles, which eventually “pop,” allowing the peptides to be released inside the cell. Credit: Ashweta Sahni

For decades, scientists have wondered how large molecules such as proteins pass through cell walls, also known as plasma membranes, without leaving a trace. That ability is part of what makes certain drugs—including some cancer treatments and the COVID-19 vaccine—work. And it is also how bacterial toxins enter human cells and wreak havoc.

One such example is , which is produced by Corynebacterium diphtheriae and causes diphtheria, a serious and potentially fatal bacterial infection of the nose and throat. But the mechanics of how these proteins enter were a scientific mystery.

A recent study, published in the journal ACS Chemical Biology, answers that mystery. The study identified the ways in which proteins cross a , a finding that could create a scientific foundation for better ways of delivering drugs into cells in the future, or for treating illnesses caused by .

“It is almost like a magic trick, the way the membrane encapsulates these toxins,” said Dehua Pei, senior author of the study and a professor of chemistry and biochemistry at The Ohio State University.

Pei’s research team at Ohio State has spent years trying to understand how biomolecules such as bacterial toxins get inside a human cell, with the goal of finding ways to get medications into those cells. It was through that work that the researchers discovered how some toxins were getting across the cell membranes, said Ashweta Sahni, lead author of the study and a graduate student in Pei’s lab at Ohio State.

Researchers have known how small molecules penetrate cell membranes, typically by binding to the membrane and then diffusing through it. But they knew that proteins do not have that ability because they are too big. Until now, the most popular hypothesis was that proteins pass through small holes, known as pores, in the membrane, akin to the Parisian statue, Le Passe-Muraille, of a man passing through a wall. But Pei’s previous work did not support that hypothesis.

While working on the team’s other projects, Sahni noticed that some fragments of proteins, known as peptides, cross membranes by pushing against them. The peptides deformed the membrane into small circular buds. The buds then detach as small bubbles, known as vesicles, which eventually “pop,” allowing the peptides to be released inside the cell. The team subsequently observed that two structurally different bacterial toxins also employed this same mechanism. This discovery led them to conclude that this budding-and-collapse mechanism is a common mechanism employed by many large biomolecules.

“This budding-and-collapse phenomenon was previously unknown, but we were able to witness it because we had the equipment, training and experience to know what we were looking at,” Sahni said.

The team witnessed the budding-and-collapse in live cells through confocal microscopy, an imaging technique that allowed them to focus in on what was happening inside the cells, and on the cell membranes, with these specific proteins.

Pei said the discovery could potentially open the door for new drug therapies that use this finding to manipulate the ways drugs enter a cell.

More information:
Ashweta Sahni et al, Bacterial Toxins Escape the Endosome by Inducing Vesicle Budding and Collapse, ACS Chemical Biology (2021). DOI: 10.1021/acschembio.1c00540

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Hexbyte Glen Cove How proteins help yeast adapt to changing conditions thumbnail

Hexbyte Glen Cove How proteins help yeast adapt to changing conditions

Hexbyte Glen Cove

Credit: CC0 Public Domain

Proteins in the brain called prions are well known for their involvement in causing disease, but a study published today in eLife suggests they may help yeast cope with rapidly changing environmental conditions.

The findings show that prions may be part of an important epigenetic mechanism for controlling in changing conditions. Further insight into this role could aid our understanding of diseases that involve abnormal cell growth or .

Prions are proteins that are abnormally folded into different shapes. Prions can spread or be passed on to new cells. They have famously been linked to two deadly brain diseases, Creutzfeldt-Jakob and Mad Cow disease. But some prions can be helpful. Each shape of prion may perform a different task in the cell, in a similar way to a Swiss Army knife.

“While scientists have known about prions for decades, we don’t yet know what distinguishes beneficial prions from harmful ones,” says co-first author David Garcia, Ph.D., who was a postdoctoral fellow at the Department of Chemical Systems Biology at Stanford University School of Medicine, California, US, and is now Assistant Professor at the Institute of Molecular Biology, University of Oregon, US.

To learn more, Garcia and colleagues studied a yeast enzyme called pseudouridine synthase that can take on two . They found that, in its alter-ego prion form, this enzyme causes yeast to multiply and grow more quickly, although these changes come at the cost of a shorter lifespan for the yeast.

Through computer modelling, the team then showed that the changes brought about by the prion are beneficial when environmental resources are abundant, but harmful when resources are scarce. By reducing a so-called protein ‘chaperone’, they also showed that the prion can revert to its original enzyme shape. Since protein chaperones themselves fluctuate during changing conditions, they propose that this might be a way to turn the prion on or off when desirable.

“We’ve identified a new role for prions in which they can transform cell growth and survival,” says co-first author Edgar Campbell, a Ph.D. student in Chemical and Systems Biology at Stanford Medicine. “These findings suggest that prions may be another form of epigenetic control of cells.”

Epigenetic changes can alter the behaviour of cells without changing their DNA, can be passed on to new generations of cells, and may be turned on or off by environmental conditions. The authors suggest that learning more about the role of prions in epigenetic control may be critical to improving our understanding of prion diseases.

“These types of epigenetic changes are missed when we sequence genomes but can still have a major influence on cell growth,” concludes senior author Daniel Jarosz, Ph.D., Associate Professor of Chemical and Systems Biology and Developmental Biology at Stanford Medicine. “It is critical to learn more about the consequences of -driven epigenetic changes in and find new ways to search for them in yeast and other organisms.”

More information:
David M Garcia et al, A prion accelerates proliferation at the expense of lifespan, eLife (2021). DOI: 10.7554/eLife.60917

Journal information:

How proteins help yeast adapt to changing conditions (2021, September 21)
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Hexbyte Glen Cove Proteins unspool DNA so cells can take on unique properties thumbnail

Hexbyte Glen Cove Proteins unspool DNA so cells can take on unique properties

Hexbyte Glen Cove

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Biologists have long wondered how complex organisms contain a variety of dramatically different types of cells with specialized functions, even though all of those cells are genetically identical.

New research reveals how proteins, called pioneer , help turn on key that give cell types their unique properties and functions.

These pioneer factors, it turns out, help unspool tightly wound coils of DNA so that genetic blueprints in genes can be read and proteins that play roles in biological processes can be made.

The study in , “Pioneer-like Factor GAF Cooperates with PBAP (SWI/SNF) and NURF (ISWI) to Regulate Transcription,” was published Dec. 10 in the journal Genes & Development.

“We know pretty well what pioneer factors are and what they do, but what we don’t know is how they work exactly,” said first author Julius Judd, a in the lab of senior author John Lis, professor of molecular biology and genetics in the College of Agriculture and Life Sciences.

In a cell’s nucleus, DNA is bound around a collection of histone proteins called nucleosomes. “DNA is wrapped around it and so the backside of the DNA is inaccessible to recognition because it’s up against these proteins,” Lis said.

As a result, the transcription factors and machinery required to read DNA sequences for making proteins can’t access these genetic codes. Genes therefore exist in a default ‘off’ state until the DNA can be accessed and the codes can be read.

In the study, the researchers focused on a suspected pioneer transcription factor found in fruit flies called GAGA-factor (GAF). Previous work in Lis’ lab has shown that GAF binds to target genes and removes nucleosomes; that exposes DNA sequences that mark where transcription of a gene begins, called a promoter sequence.

Research in other labs also suggested that GAF plays a role in embryonic development. And the researchers had evidence that GAF interacts with two different complexes called remodelers, which catalyze the process of removing the nucleosomes from DNA. All of this evidence led Lis, Judd and colleagues to believe that GAF was indeed a pioneer factor.

To test their hypothesis, Judd ran a number of different genome-wide assays to monitor transcription; how accessible the chromatin (spooled DNA) is for transcription; where GAF binds; and the cellular levels of RNA that are translated into protein. They applied these assays both to untreated Drosophila cells and cells where GAF was depleted.

The studies revealed that when GAF binds to a target gene, it recruits a remodeler called PBAP, which removes these nucleosomes and creates an accessible tract of DNA for transcription. Furthermore, at some genes nucleosomes immediately downstream of the promoter also need to be moved. In those cases, GAF relies on a different remodeler, called NURF, to push the first nucleosome along the gene out of the way to make it easier for the transcription machinery to transcribe the DNA.

“We found one pioneer factor that can interact with both remodelers and act at different steps in the process of . That is what is particularly novel,” Lis said.

Prior evidence has identified remodeling complexes almost identical to PBAP and NURF in yeast, and there are suggestions that this process occurs in mice and possibly mammals. “We think the way these remodelers are working is a deeply conserved and the conclusions are broadly applicable,” Judd said.

More information:
Julius Judd et al. Pioneer-like factor GAF cooperates with PBAP (SWI/SNF) and NURF (ISWI) to regulate transcription, Genes & Development (2020). DOI: 10.1101/gad.341768.120

Proteins unspool DNA so cells can take on unique properties (2021, January 22)
retrieved 23 January 2021
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