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Structural basis of lipid sensing in viral fusion – LISEFU

Structural basis of lipid sensing in viral fusion

This project is centered around the mechanisms of fusion of class-II fusion proteins. Enveloped viruses need to fuse their membranes with the cellular ones in order to release their genetic material into the infected cell. This process is catalyze by a specific protein termed “fusion protein”, which inserts a “fusion loop” into the target membrane. This insertion depends on the presence of specific lipids in the cellular membrane. The aim of this project is to characterize this interaction.

Structural characterization of the lipid binding pocket

There are two main objectives: <br />1) Identification of lipids compatible with binding using a liposome binding assays <br />2) Structural characterization of lipids required for fusion either by co-crystallization in presence of lipids with short-acyl chains, or in presence of detergents. We also plan to carry out structural studies using cryoEM.

We are going to use BLI to characterize the interaction with membranes and x-ray crystallography and cryoEM to perform structural studies

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In the last years, we have observed recurrent viral outbreaks around the globe due to enveloped viruses with class-II fusion machineries, specialized proteins catalysing the fusion between viral and cellular membranes. They sense the lipid composition of target membranes and fuse only those with a defined lipid composition. Single mutations altering this specificity have a great impact in virus biology and are the source of viral outbreaks, but, despite their importance, the structural basis of lipid sensing remains poorly understood. We have determined the structure of a class-II fusion protein in complex with a lipid identifying the molecular determinants of lipid specificity and showing the existence of a structurally conserved lipid-binding pocket across class-II fusion proteins. This proposal aims to take advantage of the momentum generated by this finding to understand the lipid sensing mechanism in class-II mediated viral fusion by combining structural approaches (x-ray crystallography and electron cryo-microscopy) and functional studies (membrane binding screening and fusion of VLPs to liposomes) to understand the molecular determinants of lipid sensing in different class-II fusion proteins. THe long term goal of the proposal is to find small molecules targeting this pocket that could act as broad spectrum antivirals.

Project coordinator

Monsieur PABLO GUARDADO CALVO (INSTITUT PASTEUR)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP INSTITUT PASTEUR

Help of the ANR 283,505 euros
Beginning and duration of the scientific project: February 2019 - 36 Months

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