8ILC

Crystal structure of Se-Met CoV-Y domain of Nsp3 in SARS-CoV-2

Summary for 8ILC

• Entry DOI: 10.2210/pdb8ilc/pdb
• Descriptor: Papain-like protease nsp3, SULFATE ION, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: severe acute respiratory syndrome coronavirus 2, nonstructural protain3, y domain, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 32034.87

Authors

Wang, K.,Nan, J.,Lei, J. (deposition date: 2023-03-03, release date: 2023-05-24, Last modification date: 2024-10-23)

Primary citation

Wang, K.,Ni, X.,Deng, X.,Nan, J.,Ma-Lauer, Y.,von Brunn, A.,Zeng, R.,Lei, J.
The CoV-Y domain of SARS-CoV-2 Nsp3 interacts with BRAP to stimulate NF-kappa B signaling and induce host inflammatory responses.
Int.J.Biol.Macromol., 280:136123-136123, 2024

PubMed Abstract: Non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome. It consists of multiple domains that perform critical functions during the viral life cycle. CoV-Y is the most C-terminal domain of Nsp3, and it exhibits evolutionary conservation across diverse CoVs; however, the exact biological function of CoV-Y remains unclear. Here, we determined the crystal structure of CoV-Y of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp3 using the single-wavelength anomalous diffraction method. We revealed the interaction between CoV-Y and the host BRCA1-associated protein (BRAP) using immunoprecipitation-mass spectrometry experiments. This interaction was subsequently confirmed in cellular assays, and the precise binding-regions between these two proteins were clarified. We found that this interaction is conserved in SARS-CoV and Middle East respiratory syndrome coronavirus. Next, we demonstrated that CoV-Y enhances IκBα and IκBβ phosphorylation and promotes the nuclear translocation of the downstream NF-κB members p50 and p65 through binding to BRAP. The CoV-Y-BRAP interaction can upregulate the transcript levels of the host inflammatory cytokines. Overall, our findings illustrate the biological function of CoV-Y for the first time and provide novel insights into coronavirus regulation of host inflammatory responses, as well as a possible target for antiviral drug development.

PubMed: 39343285
DOI: 10.1016/j.ijbiomac.2024.136123

Experimental method

X-RAY DIFFRACTION (2.2 Å)