First Fully Visualized Protein Associated with Many Diseases

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5 years ago

New drugs can be motivated by understanding how receptors of P2X7 proteins function.

Scientists first noticed how a protein associated with various health issues functions at the molecular level.

The breakthrough, that one day could inspire new drugs to treat inflammation, coronary artery disease, leukemia, multiple sclerosis, and more, has been published today in the Cell journal.

Research assistant at Oregon Health & Science University Alanna McCarthy, B.S., and scientist at OHSU Steven Mansoor, M.D., Ph.D., used cryoelectron microscopy to obtain a protein receptor’s 3D structure and observe its inner working. The protein receptor they studied is a protein of the cell membrane that enables electrically charged particles of sodium and calcium to enter and cause changes in a cell.

They specifically studied the P2X7 receptor, a subtype associated with inflammation of the ligand-gated ion channel P2X family, plaque buildup in arteries, metastasis of cancer, neurological conditions, and more.

P2X7 is unique because its channel remains open indefinitely once it is activated, allowing continuously charged particles to enter a cell and initiate the inflammation signaling pathways, ultimately resulting in cell death. These signaling activity may contribute to the receptor-related long list of ailments.

Unlike previous efforts to image the P2X7 receptor, they were able to capture the protein receptor in its entirety through the cryo-EM imaging approach of the team.

This helped them to imagine the receptor sections inside the cell that were sitting. As a result, they can specifically analyze how fatty acid molecules called palmitoyl groups change these parts. When these groups were eliminated by Mansoor and his colleagues, they found that the receptor was no longer open indefinitely, shutting down their ability to trigger signaling. He also found suddenly that a guanosine nucleotide inside the cell was bound to P2X7.

“Researchers have known ligand-gated ion channels are modified by palmitoyl groups, but we had never directly observed it until now,” said Mansoor, an assistant professor of medicine (cardiovascular) in the OHSU School of Medicine and Knight Cardiovascular Institute. “Our finding could be used as a model of how palmitoylation modifies other ion channels.”

Mansoor and his team will further explore the roles that palmitoyl groups and the guanosine nucleotide play in P2X7 intra-cellular signaling, their potential impact on human health, and how they could be targeted to treat health conditions associated with the receptor.

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This research was supported by the National Heart, Lung and Blood Institute (grant K99HL138129). The team used microscopes at the Pacific Northwest Center for Cryo-EM, which OHSU and Pacific Northwest National Laboratory established in 2018 with support of the National Institutes of Health, and conducted research in the OHSU Vollum Institute lab of Eric Gouaux, Ph.D., who is supported by the Howard Hughes Medical Institute.

REFERENCE: Alanna E. McCarthy, Craig Yoshioka, Steven E. Mansoor, Full-length P2X7 structures reveal how palmitoylation prevents channel desensitization, Cell, 11 a.m. ET Oct. 3, 2019, DOI: 10.1016/j.cell.2019.09.017, https://www.cell.com/cell/fulltext/S0092-8674(19)31068-2