RESEARCH SUMMARY

A large variety of glycosylated proteins participating in cell-cell and virus-cell interactions populate the cellular and viral membranes. The surface proteins communicate the cell with its environment and participate in cell emigration and in virus entry processes.

Our group researches on receptor-ligand recognition using biochemical techniques and X-ray crystallography, studying receptors of the immune system, some of which have been subverted by viruses to enter into host cells. So, our research focuses also in receptor-mediated virus entry into cells, with viruses of medical interest using the receptor molecules for attachment and cell membrane penetration. We investigate receptor recognition and the dynamics of virus entry with rhinovirus, measles virus and coronavirus.

Our research provides new knowledge on cell adhesion and virus entry processes and is relevant for the development of anti-viral therapies and treatments of immune disorders.

Some of our recent results, related to both immune processes and viral infections, are highlighted below:

The T-cell/Transmembrane, Immunoglobulin and Mucin domain (TIM) gene family plays a critical role in regulating immune responses, including transplant tolerance, autoimmunity, the regulation of allergy and asthma, and the response to viral infections.

We have demonstrated that the TIM proteins are pattern recognition receptors specialized in the recognition of the phosphatidylserine (PtdSer) cell death signal.

The figure on the left shows a surface representation of the structure of the mTIM-4 IgV domain bound to PtdSer in a phospholipid membrane bilayer, structure determined in our laboratory. Cells expressing TIM-1, TIM-3 and TIM-4 can mediate the elimination of apoptotic cells, which expose PtdSer on the outer membrane leaflet.

This biological process is essential for maintaining tissue homeostasis and the prevention of autoimmunity and inflammatory reactions.

Measles Virus binding to the CD46 cellular receptor

Measles virus (MV) has a glycoprotein anchored to its lipid envelope known as hemagglutinin (H). The H protein is specialized in the recognition of cell surface receptor molecules such as CD46. This process is essential for virus entry into host cells. We have been able to visualize this molecular event by determining the crystal structure of the measles virus H protein bound to the CD46 receptor protein. The image on the right shows a surface representation of the dimeric H protein structure (rainbow coloring) bound to two CD46 molecules (C alpha trace in blue). Electron microscopy image of measles virus particles entering in a cells is shown bellow the structure representation. Binding to the CD46 receptor molecule is essential for MV entry into human cells and it begins the virus infective cycle.