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bioRxiv · 10.1101/2024.02.07.579372

The nanoscale organization of the Nipah virus fusion protein informs new membrane fusion mechanisms.

Wang, Q.·Liu, J.·Luo, Y.·Kliemke, V.·Matta, G. L.·Wang, J.·Liu, Q.
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Abstract

Paramyxovirus membrane fusion requires an attachment protein for receptor binding and a fusion protein for membrane fusion triggering. Nipah virus (NiV) attachment protein (G) binds to ephrinB2 or -B3 receptors, and fusion protein (F) mediates membrane fusion. NiV-F is a class I fusion protein and is activated by endosomal cleavage. The crystal structure of a soluble GCN4-decorated NiV-F shows a hexamer-of-trimer assembly. Here, we used single-molecule localization microscopy to quantify the NiV-F distribution and organization on cell and virus-like-particle membranes at a nanometer precision. We found that NiV-F on biological membranes forms distinctive clusters that are independent of endosomal cleavage or expression levels. The sequestration of NiV-F into dense clusters favors membrane fusion triggering. The nano-distribution and organization of NiV-F are susceptible to mutations at the hexamer-of-trimer interface, and the putative oligomerization motif on the transmembrane domain. We also show that NiV-F nanoclusters are maintained by NiV-F-AP-2 interactions and the clathrin coat assembly. We propose that the organization of NiV-F into nanoclusters facilitates membrane fusion triggering by a mixed population of NiV-F molecules with varied degrees of cleavage and opportunities for interacting with the NiV-G/receptor complex. These observations provide insights into the in-situ organization and activation mechanisms of the NiV fusion machinery.

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Wang, Q., Liu, J., Luo, Y., Kliemke, V., Matta, G. L., Wang, J., Liu, Q.. 2024-02-08. The nanoscale organization of the Nipah virus fusion protein informs new membrane fusion mechanisms.. https://doi.org/10.1101/2024.02.07.579372

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