Our Immune System Is No Match – Coronavirus Protein Caught Severing Critical
This image shows the SARS-CoV-2 virus’s main protease, Mpro, and two strands of a human protein, called NEMO. One NEMO strand (blue) has been cut by Mpro, and the other NEMO strand (red) is in the process of being cut by Mpro. Without NEMO, an immune system is slower to respond to increasing viral loads or new infections. Seeing how Mpro attacks NEMO at the molecular level could inspire new therapeutic approaches. Credit: Greg Stewart/SLAC National Accelerator Laboratory
Powerful X-rays from the SLAC synchrotron show that the fundamental wiring of our immune system seems to be no match for the vicious Department of Energy’s SLAC National Accelerator Laboratory have now seen one of the virus’s most crucial interactions for the first time, which might aid in the development of more precise treatments.
The researchers captured the moment when a viral protein called Mpro slashes a protective protein called NEMO in an infected individual. Without NEMO, the immune system is slower to react to growing viral loads or new infections. Understanding how Mpro targets NEMO at the molecular level may provide new treatment strategies.
Researchers exposed crystalline samples of the protein complex to intense X-rays from SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) to see how Mpro cuts NEMO. The protein samples were hit by X-rays, which showed what Mpro looks like when it disables NEMO’s primary function of facilitating immune system communication.
This image shows how SARS-CoV-2 Mpro recognizes and cuts NEMO based on the crystal structure determined using a powerful X-ray beam at SSRL Beam Line 12-2. Credit: SLAC National Accelerator Laboratory
“We saw that the virus protein cuts through NEMO as easily as sharp scissors through thin paper,” said co-senior author Soichi Wakatsuki, professor at SLAC and Stanford. “Imagine the bad things that happen when good proteins in our bodies start getting cut into pieces.”
The images from SSRL provide the first structure of SARS-CoV-2 Mpro bound to a human protein and show the precise location of NEMO’s cut.
“If you can block the sites where Mpro binds to NEMO, you can stop this cut from happening over and over,” SSRL lead scientist and co-author Irimpan Mathews said. “Stopping Mpro could slow down how fast the virus takes over a body. Solving the crystal structure revealed Mpro’s binding sites and was one of the first steps to stopping the protein.”
The research team from SLAC, DOE’s Oak Ridge National Laboratory, and other institutions recently published their results in the journal
Protecting an immunity pathway
NEMO is part of a human immune system known as the NF-κB pathway. You can think of NEMO and the NF-κB pathway as if they were a card reader and wiring on the outside of a locked building entrance door. If the wires to the card reader are cut, the door will not open, meaning a person (or an immune system activator, like NEMO) is stuck outside, unable to do whatever they came to do.
Researchers stand near SSRL’s Beam Line 12-2. From left, Mikhail Hameedi, SLAC scientist and co-first author; Soichi Wakatsuki, co-senior author and professor at SLAC and Stanford; and Irimpan Mathews, SSRL lead scientist and co-author. Credit: Jacqueline Ramseyer Orrell/SLAC National Accelerator Laboratory
The NF-κB pathway is a critical part of protective inflammatory responses. When NEMO is cut, our immune response can’t be activated, resulting in various detrimental effects on our body. COVID-19 viral infections could be made worse if Mpro destroys NEMO, helping the virus evade our innate immune responses. Additionally, a separate study by researchers at institutions in Germany found that the loss…
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