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Scientists discover how COVID-19 damages human lungs

Artist showing lung disease

The new structure shows how proteins from the viral shell hijack proteins that separate cells and promote viral proliferation. The findings could accelerate drug design to prevent the deadly effects of Covid-19.

Scientists at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory have published the first detailed atomic-scale model of SARS-CoV-2 A protein “envelope” that binds to human proteins that are essential for maintaining the lining of the lungs. The model shows how the two proteins interact. just published in the journal nature communicationHelp explain how the virus can cause extensive lung damage and escape the lung to other organs. especially those with high-risk COVID-19 patients. The findings may accelerate the search for drugs to prevent the most severe effects of the disease.

Qun Liu, a structural biologist at Brookhaven Lab, said: “Getting atomic-level details of protein interactions is a very important way to achieve this.” We can explain why the damage happened. and look for inhibitors that can specifically block these interactions. Viruses won’t do much damage. That could give people in poor health a greater chance for their immune system to successfully fight the virus.”

COVID-19 virus envelope protein

The new structure shows how the COVID-19 viral sheath protein (E, magenta bar) interacts with human cell interface proteins (PALS1, blue, green, and orange substrate). understand this complex structure. This was resolved with cryogenic electron microscopy at Brookhaven National Laboratory. It could lead to the discovery of drugs that block interactions and potentially have the most serious effects of COVID-19. Credit: Brookhaven National Laboratory.

Scientists have discovered in detail and developed a molecular model using one of the cold electron microscopes at Brookhaven Lab for Biological Molecular Structures (LBMS), a new research facility built with New York State funding. adjacent to Brookhaven’s National Synchrotron Light Source (NSLS)-II).

Sean McSweeney, LBMS director and co-author on the paper, said: “LBMS opened early last summer. Due to their importance in the fight against COVID-19, “LBMS and NSLS-II offer complementary protein imaging techniques. And both have played a key role in deciphering the details of proteins associated with COVID-19. This is the first document published based on results from a new plant.”

“Scanning electron microscopy (cryo-EM) is particularly useful for studying membrane proteins and transmembrane protein complexes,” explains Liguo Wang, director of scientific operations at LBMS and another co-author on the paper. dynamic This can be difficult to crystallize for protein crystals. General techniques for studying protein structure with this technique So we created a 3D map where we could see how the individual protein components fit together.”

“Without cryo-EM, we cannot have structures to capture the dynamic interactions between these proteins,” Liu said.

stimulate pulmonary disruption

The envelope protein SARS-CoV-2 (E), found on the viral outer membrane, coupled with the now-infamous coronavirus spike protein. Help collect new virus particles within the infected cells. A study published early in the COVID-19 pandemic shows that it also plays an important role in hijacking human proteins to facilitate the release and spread of the virus. Scientists hypothesize this is accomplished by binding to proteins from human cellular junctions. Pull them out of the normal job of keeping the junctions between the lung cells tight.

“Such interactions could have a positive effect on the virus. and have a detrimental effect on humans especially elderly COVID-19 patients and those with pre-existing medical conditions,” Liu said.

COVID-19 virus envelope protein

Close-up of the COVID-19 viral sheath protein (magenta) and its interaction with the specific amino acid that forms hydrophobic pockets on PALS1 (blue, green, and orange). Credit: Brookhaven National Laboratory.

when the lung cell junction is interrupted Immune cells will try to fix the damage. By releasing small proteins called cytokines. This immune response can be made worse by causing massive inflammation, causing a “cytokine storm” and subsequent acute respiratory distress syndrome.

Additionally, because of this damage, the cell-to-cell connection is weakened. It may make it easier for the virus to escape from the lungs and travel through the bloodstream to infect other organs, including the liver, kidneys and blood vessels.

“In this situation Most of the damage will occur in patients with more virus and more protein E production,” Liu said. And this could turn into a vicious cycle: more viruses cause more E protein and cell-isolation proteins are pulled. come more cause more damage more contagious And more viruses. In addition, any damage that exists, such as scars from the lung cells. It may make it harder for COVID patients to recover from damage.

“That’s why we wanted to study this interaction – to understand in atomic-level detail how E interacts with human proteins, to learn how to disrupt the interactions and reduce or prevent these extreme effects,” Liu said.

from point to point to the map to the model

By mixing the two proteins together, the scientists obtained atomic-level details of the interactions between E and human lung cell-linking proteins called PALS1. Quickly Freeze Samples The cryo-EM frozen sample is then studied. Electron microscopy uses high-energy electrons to interact with the sample in the same way that a conventional optical microscope uses a beam. But electrons allow scientists to see things on a much smaller scale. because the wavelength is very short ( 100,000 times shorter than visible light)

The first image doesn’t look like a dot. But the image-processing technique allowed the team to spot the true complexes of the two proteins.

Decode the structure of the human-binding COVID-19 E virus protein PALS1.

Decoding the structure of the human PALS1-binding COVID-19 virus E protein: initiated with cryo-EM micrographs resolved with granular nanometer-scale dot motion. The two-dimensional mean results in a low-resolution projection of The bound proteins from different directions (b) the computational tool converted these 2D images into three-dimensional maps. (c) Blue represents the fragments with the highest resolution and stability. and red indicates lower resolution parts that are more flexible. This map provides sufficient detail to fit the amino acid formation of the two proteins in the final structure of the complex (d), where PALS1 parts are shown in blue, green, and orange and viral protein E is. Magenta. Credit: Brookhaven National Laboratory.

“We used two-dimensional averaging and began to see some structural features shared between these particles. Our images show complexity from different orientations. “We then used the computational tools and computational infrastructure at Brookhaven’s Computer Science Initiative to reconstruct the three dimensions. This gives us a 3D model — an experimental map of the structure.”

With an overall resolution of 3.65 angstroms (just a few atoms in size), the map contains enough information about individual characteristics.

Amino acids are a collection of organic compounds used to make proteins. There are about 500 known amino acids, although only 20 appear in the genetic code. Proteins are made up of one or more chains of amino acids called polypeptides. The sequence of amino acid chains causes polypeptides to fold into bioactive shapes. The amino acid sequence of proteins is encoded in genes. The nine amino acids that make up proteins are called “essential” for humans because they cannot be produced from other compounds by the human body and must be taken as food.

” class=”glossaryLink “>Amino acids that make up both proteins for scientists to fit the known structures of those amino acids into the map.

“We can see how the amino acid chains that make up the PALS1 protein fold into three structural components, or domains. and the much smaller chains of amino acids that make up protein E fit in the hydrophobic pockets between these two domains,” Liu said.

The model provides both structural details and an understanding of the intermolecular forces that allow the E protein deep inside the infected cell to pull PALS1 out of its location at the cell’s outer boundary.

“Now we can explain how the interaction pulls PALS1 from human lung cell junctions and contributes to the damage,” Liu said.

Implications for Medicine and Evolution

“This structure lays the foundation for our computer science colleagues to conduct connectivity studies and molecular simulations to find drugs or drug-like molecules that may block interactions,” said John Shanklin, Head of Biology. of Brookhaven Lab and co-authors on the paper. We will have the ability to analyze for rapid screening through such optional drugs. to identify that could be key to preventing the deadly consequences of COVID-19.”

Understanding the dynamics of this protein interaction will help scientists track how viruses such as SARS-CoV-2 develop.

“When viral proteins pull PALS1 out of the cell junction, It will help the virus spread more easily. That would provide an advantage in choosing for any virus trait that increases its survival. spread or the release of the virus is likely to be preserved,” Liu said.

The longer the virus spreads The greater the opportunity for new evolutionary advantages. only more

“This is another reason it’s extremely important that we identify and use promising treatments,” Liu said. We are ahead of these mutations.”

Cited from: June 8, 2021, nature communication.
DOI: 10.1038/s41467-021-23533-x

This research was funded by Brookhaven National Laboratory’s COVID-19 Laboratory Directed Research and Development (LDRD) Fund. The LBMS is supported by the DOE Office of Science (BER). NSLS-II is a DOE user facility. Office of Science, which is supported by the Office of Science (BES).

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