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A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion

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Science  03 Nov 2017:
Vol. 358, Issue 6363, pp. 663-667
DOI: 10.1126/science.aal2712

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Unmasking class II membrane fusion

Rift Valley fever virus (RVFV) is transmitted by mosquitos and enters cells through receptormediated endocytosis. The infection process requires class II membrane fusion proteins, which insert a hydrophobic fusion loop into cell membranes and then refold. Guardado-Calvo et al. report the high-resolution crystal structure of RVFV class II fusion protein Gc in its postfusion form complexed with phosphatidylcholine. They find that Gc does not restructure its fusion loop after insertion. Rather, it uses an integrated system that accommodates glycerophospholipid head groups and then initiates membrane reorganization by concentrating cholesterol at the insertion site. Comparison with class II fusion proteins from other virus families suggests a common mechanism, which may provide a target for future antiviral therapies.

Science, this issue p. 663

Abstract

The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

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