The Kaposi's sarcoma herpesvirus causes skin cancers, especially in immunocompromised people. A recent study offers new modellings of one of the virus’ a surface proteins, and its receptor, on human cells.
Some cancers are caused by a viral infection. This is the case with Kaposi's sarcoma, a disease that manifests as skin lesions, but can also affect organs, such as the lungs. It particularly threatens immunocompromised people, especially those infected by HIV, but also children and men in sub-Saharan Africa, where the virus is endemic. In order to better treat this disease, it is essential to understand the functioning of Kaposi’s sarcoma-associated herpesvirus (KSHV), which causes it. A study in which the Structural Virology team at the Institut Pasteur participated investigates the way this herpesvirus manages to infect human cells.
In order to multiply, KSHV must, like all viruses, get its genetic material into a cell, which can transcribe it into proteins that can be assembled into new viruses. It must therefore succeed in fusing its own membrane with that of the target cell. The article shows how the virus interacts with a receptor on human cells, the EphA2 receptor, via a surface protein complex made of glycoproteins H and L (gH/gL). The gH/gL complex has a structure that mimics ephrins, the proteins that naturally bind to the EphA2 receptor. This tricks the receptor into allowing viral entry.
Thanks to protein crystallization, carried out using the Institut Pasteur's High-Throughput Crystallization Screening platform, and X-ray diffraction data collected at the SOLEIL French national synchrotron source, the researchers were able to obtain the precise three-dimensional structure of the viral gH/gL complex bound to the EphA2 receptor. The Molecular Biophysics platform was also involved. These advances provide a roadmap for determining a way to block the interaction between the virus protein and the receptor.
This study is part of the priority scientific area Emerging infectious diseases of the Institut Pasteur's strategic plan for 2019-2023.
Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling, PLOS Biology, september 9, 2021
Taylor P. Light1,2, Delphine Brun3,4, Pablo Guardado-Calvo3,4, Riccardo Pederzoli3,4, Ahmed Haouz4,5, Frank Neipel5, Félix A. Rey3,4, Kalina Hristova1,2, Marija Backovic3,4
1 - Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland, United
States of America
2 - Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland, United
States of America
3 - Department of Virology, Structural Virology Unit, Institut Pasteur, Paris, France,
4 - CNRS, UMR 3569, Paris, France
5 - Crystallography Platform C2RT, Institut Pasteur, Paris, France
6 - Virologisches Institut, Universitaetsklinikum Erlangen, Erlangen, Germany