Our Immune System Isn’t Up to the Task – Coronavirus Protein Caught Breaking a Critical Immunity Pathway

Mpro, the primary protease of the SARS-CoV-2 virus, and two strands of NEMO, a human protein. Mpro has cut one NEMO strand (blue), and Mpro is currently cutting the other NEMO strand (red).

The SLAC synchrotron’s powerful X-rays show that our immune system’s fundamental wiring appears to be no match for the vicious SARS-CoV-2 protein.

Scientists have thoroughly examined the SARS-CoV-2 virus over the last two years, laying the groundwork for COVID-19 vaccinations and antiviral therapies. For the first time, researchers at the Department of Energy’s SLAC National Accelerator Laboratory have observed one of the virus’s most critical interactions, which could aid in the development of more specific treatments.

Researchers looked at how a viral protein called Mpro cuts a protective protein called NEMO in an infected person. Without NEMO, the immune system responds slowly to increasing viral loads or new infections. Understanding how Mpro targets NEMO at the molecular level may lead to new treatment options.

To determine how Mpro reduced NEMO, researchers exposed crystalline portions of the protein complex to intense X-rays from SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL). X-rays were used to examine the protein samples, which revealed what Mpro looks like when it disrupts NEMO’s primary function of facilitating immune system communication.

Based on the crystal structure determined by a powerful X-ray beam at SSRL Beam Line 12-2, SARS-CoV-2 Mpro recognizes and cuts NEMO. Photographer: SLAC National Accelerator Laboratory

“We discovered that the virus protein cuts through NEMO as easily as sharp scissors through thin paper,” said co-author Soichi Wakatsuki, a SLAC, and Stanford professor. “Imagine the devastation that occurs when good proteins in our bodies begin to break down.

The SSRL images show the first structure of SARS-CoV-2 Mpro bound to a human protein and the precise location of NEMO’s cut.

Irimpan Mathews, an SSRL lead scientist, and co-author believes that blocking Mpro’s binding sites will prevent the virus from reoccurring. One of the first steps in stopping the protein was to solve the crystal structure, which revealed Mpro’s binding sites.

Their findings from SLAC, the United States’ Oak Ridge National Laboratory, and other organizations were recently published in the journal Nature Communications.

The NF-B pathway is a component of the human immune system that operates at a locked building entrance door. If the NEMO or an immune system activator is cut, the entrance door will not open, leaving a person (or an immune system activator, such as NEMO) outside, unable to do what they have chosen.

Researchers pose near Beam Line 12-2 at SSRL. Mikhail Hameedi, SLAC scientist and co-first author; Soichi Wakatsuki, SLAC and Stanford professor; and Irimpan Mathews, SSRL lead scientist, and coauthor

COVID-19 viral infections may be enhanced if Mpro destroys NEMO, aiding the virus in evading our innate immune responses, according to the researchers. Additionally, the loss of NEMO by Mpro might lead to damage in some brain cells, which might explain neurological symptoms experienced in COVID-19 patients.

Our Immune System Isn't Up to the Task - Coronavirus Protein Caught Breaking a Critical Immunity Pathway

One medication that is currently approved for emergency use targets Mpro proteins by providing a Mpro inhibitor to an infected person. This kind of inhibitor drug may be enhanced now that the location of the cut has been identified.

Mikhail Ali Hameedi, a SLAC scientist and co-first author, said the crystal structures of NEMO and Mpro provide us with targets to develop therapies that prevent these cuts from happening. “Seeing the molecular details of how Mpro attacks NEMO will help us develop new therapies in the future as Mpro mutates.”

SARS-CoV-2 is the most effective at attaching to and cutting NEMO, according to the researchers. Hundreds of other critical proteins in human host cells, such as those associated with blood disorders, are also being improved by SARS-CoV-2.

Researchers utilized the Summit supercomputer at the Oak Ridge Leadership Computing Facility to forecast how well Mpro binds to NEMO. They combined molecular dynamics simulations with five machine learning models in a novel way and applied quantum chemistry, finding that Mpro has the highest binding affinity in SARS-CoV-2 compared to the other primary coronaviruses.

Erica Prates, co-first author and ORNL scientist, was able to anticipate the strongest binding spots between NEMO and Mpro using a set of computational methods. “We believe that a high binding affinity at these hot sites contributes to the virus’s high fitness in humans.”

According to Wakatsuki, the biomedical business may leverage the research to develop better inhibitor medications and better understand how other proteins may be affected by Mpro.

“NEMO is only the tip of the iceberg,” he added. “We can now investigate what happens when many other proteins in the body are cleaved by Mpro during infection.”

Mikhail A. Hameedi, Erica T. Prates, Michael R. Garvin, Irimpan I. Mathews, B. Kirtley Amos, Omar Demerdash, Mamta Iyer, Simin Rahighi, Daniel W. Kneller, Andrey Kovalevsky, Julie C. Mitchell, Audrey Labbe, Soichi Wakatsuki, and Daniel Jacobson, 8 September 2022, Nature Communications. DOI: 10.1038/s

The National Institutes of Health and the National Institute of General Medical Sciences provided assistance to this study. SSRL is a facility used by the Office of Science.

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