Scientists identify a mechanism used by a family of viruses to initiate infections

It has been possible to identify a conserved biological function in an adenovirus protein, which is required for the initiation of the infectious process. Most of these pathogens do not cause serious illness in humans, but are associated with respiratory tract problems such as pneumonia, as well as gastroenteritis, conjunctivitis, and hepatitis, among others.

The substance studied belongs to a class of proteins called “intrinsically disordered” (IDPs) that, with the development of new technologies, have begun to be better studied in recent years.

The research has been carried out by a team from the National Council for Scientific and Technical Research (CONICET) in Argentina.

“Our work describes a conserved molecular mechanism in adenoviruses, but suggests that it is worth investigating whether this mechanism is also conserved in other PIDs involved in infections caused by many viruses, in normal cell function, and in diseases such as cancer, Parkinson’s, Alzheimer’s and others. If so, this knowledge could be extrapolated to understand how this new class of proteins works, and help in the search for novel therapies to inactivate PIDs and treat multiple diseases”, says Lucía Chemes, director of the study, CONICET researcher and head of the Laboratory of Structure, Function and Plasticity of Proteins of the Biotechnological Research Institute (IIBiO), dependent on CONICET and UNSAM).

IDPs include many proteins important to health. For example, amyloid beta protein and alpha-synuclein are IDPs that play a central role in Alzheimer’s and Parkinson’s disease, respectively. Many viruses use IDPs to initiate infectious processes that can lead to the development of cancer. “One of these cases is the E7 oncoprotein of the Human Papilloma Virus (HPV). This IDP inactivates the cellular protein Retinoblastoma (Rb), which is a tumor suppressor and causes cancer of great importance for health, such as cervical cancer”, adds Nicolás González Foutel, first author of the work, who was part of his doctoral thesis, and now a postdoctoral fellow at the Department of Molecular Biology and Genetics at Aarhus University, Denmark.

Like HPV, adenoviruses inactivate Rb as a preliminary step to replicate the viral genome and initiate the infectious process within infected cells. Now the work led by Chemes explains at the molecular level how the IDPs of an entire family of adenoviruses bind to Rb with high affinity, to block its activity.

The CONICET specialists used as a study model the interaction of the E1A protein (in red and blue) of adenovirus with Rb (gray color), a cellular protein that suppresses tumors. (Photo: CONICET)

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The CONICET specialists used as a study model the interaction of the intrinsically disordered protein E1A of “human adenovirus 5” with Rb. First, they carried out in vitro studies with both purified proteins and measured the interaction strength between both proteins. “This force is known as affinity and we analyze it in detail at the molecular level”, highlights González Foutel.

Using structural biology methods such as nuclear magnetic resonance and X-ray scattering, the research team was able to demonstrate that the E1A protein uses two regions called “linear motifs” (SLiMs) to interact with Rb . The linear motifs are linked by a flexible region, called “linker”, which allows both motifs to cooperate with each other to bind Rb. This tethering mechanism explains how E1A manages to bind with high affinity to Rb and inactivate it.

In additional experiments, the CONICET research team found that the affinity of E1A from other adenoviruses for Rb was similar. “The results indicated that this protein uses the same ‘anchoring’ mechanism in different adenoviruses”, says Chemes.

“On the other hand, using bioinformatic tools, we were able to generalize the experimental discoveries to a family made up of a hundred adenoviruses that infect humans and other mammals,” highlights Juliana Glavina, also the first author of the study and a CONICET postdoctoral fellow at the IIBiO.

“We were able to show that the disordered and flexible nature of E1A was essential for the ‘docking’ mechanism of this family of adenoviruses. In addition, the results suggest that this mechanism could be conserved in many other IDPs”, adds Chemes.

Although the development of drugs against PIDs is in early stages, it is possible that the knowledge of the mechanisms described in the study led by the CONICET specialists will help in the future design of novel drugs. “For example, drugs that stabilize the tumor suppressor protein Rb, or inhibitors of PIDs that inactivate Rb, could be a desirable goal in the fight against cancer. The results of our work provide data that stimulate a wide range of research that can begin to answer these questions”, concludes Chemes.

The study is titled “Conformational buffering underlies functional selection in intrinsically disordered protein regions.” And it has been published in the academic journal Nature Structural & Molecular Biology. (Source: Bruno Geller / CONICET. CC BY 2.5 AR)