NMR solves retroviral mystery: Avian Sarcoma Virus

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  • Published: Jan 7, 2019
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: NMR solves retroviral mystery: Avian Sarcoma Virus

Chicken cancer

Pekin bantam photo by David Bradley NMR spectroscopy has been used to reveal molecular details of a key step in retroviral growth within the cell. The study shows how the matrix domain of the avian sarcoma virus, or ASV, Gag protein binds to certain phospholipids, which are critical to binding to the plasma membrane of a cell for viral replication.

Nuclear magnetic resonance (NMR) spectroscopy has been used to reveal molecular details of a key step in retroviral growth within the cell. The study shows how the matrix domain of the avian sarcoma virus, or ASV, Gag protein binds to certain phospholipids, which are critical to binding to the plasma membrane of a cell for viral replication. The work solves a mystery surrounding this virus, which was discovered more than a century ago, and could have implications for understanding the replication of other retroviruses, such as Human Immunodeficiency Virus, HIV.

ASV causes cancer in chickens and so is an important virus in veterinary science and poultry farming. It is also important as being the first oncovirus discovered more than a century ago and belongs to a broad group of viruses, the retroviridae family, and so is used as a model to study mechanisms of retroviral infection and replication. By studying the behaviour and molecular biology of ASV and comparing them to other retroviruses, such as HIV, researchers can glean basic knowledge about the diseases these viruses cause and perhaps find ways to treat them and even halt their spread. Now, Jamil Saad of the University of Alabama at Birmingham and colleagues hope to fill some of the gaps in our knowledge about retrovirus replication.

Gag order

Work led by Saad and a parallel study by Carol Carter and her team at Stony Brook University has looked at how the ASV Gag protein is targeted to the plasma membrane of the host cell to initiate virus assembly. The results show the plasma membrane binding by the matrix domain of Gag, all the way from determining the precise molecular shape of the protein domain to studying its vital activity in living cells to initiate viral budding. Saad and colleagues elucidated the molecular determinants of ASV matrix interaction with lipids and membranes, and they provided a model of how the matrix binds to a cell membrane. This significantly improves our structural model of the matrix domain as well as identifying a membrane binding site that was not obvious from previous structural studies.

HIV parallels

In addition, the work provides compelling new evidence that a cluster of four lysine amino acids in the matrix domain create a basic surface, which acts as a single binding site that directly interacts with acidic membrane lipids called phosphoinositides. Indeed, replacing the lysine residues in the binding site of matrix with a different amino acid greatly diminishes binding to lipids and membranes. The work also demonstrates that the Gag-membrane interaction is governed by charge-charge interactions.

Carter's research used mutations in the matrix domain of the ASV Gag protein to show that disruption of the phosophoinositide binding site on the matrix domain inhibited Gag localization at the cell periphery in two different cell lines and severely reduced viral particle production, as compared with unmutated ASV.

"These studies solved a longstanding mystery on how a virus discovered a century ago utilizes the plasma membrane of the host cell to replicate," Saad explains. "What is even more remarkable is how ASV and HIV-1 share very similar structural features that drive membrane targeting and assembly."

Related Links

J. Biol. Chem., 2018, online: "Structural basis for targeting avian sarcoma virus Gag polyprotein to the plasma membrane for virus assembly"

J. Biol. Chem., 2018, online: "The matrix domain of the Gag protein from avian sarcoma virus contains a PI(4,5)P2-binding site that targets Gag to the cell periphery"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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