National Academy of Sciences, Proceedings of the National Academy of Sciences, 1(118), 2020
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Significance Most cell-cell fusogens have tall ectodomains that drive fusion by undergoing conformational changes that pull two membranes together, akin to the mechanism used by viral fusogens during enveloped virus entry. In contrast, fusion-associated small transmembrane (FAST) proteins from reovirus have short, structurally minimal, membrane-disruptive ectodomains. In this work, we show that evolutionarily distant FAST proteins from aquareovirus and orthoreovirus use different adaptor proteins to hijack host actin assembly and push two membranes together during cell-cell fusion. Despite minimal sequence similarity, the cytoplasmic tails from divergent FAST proteins can be functionally exchanged and even replaced with different actin nucleators while maintaining fusogenicity. This feature suggests a conserved biophysical strategy shared by FAST proteins that could be used by other cell-cell fusogens.