Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery

Vidya Mangala Prasad, Jelle S. Blijleven, Jolanda M. Smit and Kelly K. Lee ()
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Vidya Mangala Prasad: University of Washington
Jelle S. Blijleven: University of Groningen
Jolanda M. Smit: University of Groningen, University Medical Center Groningen
Kelly K. Lee: University of Washington

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Chikungunya virus (CHIKV) is a human pathogen that delivers its genome to the host cell cytoplasm through endocytic low pH-activated membrane fusion mediated by class-II fusion proteins. Though structures of prefusion, icosahedral CHIKV are available, structural characterization of virion interaction with membranes has been limited. Here, we have used cryo-electron tomography to visualize CHIKV’s complete membrane fusion pathway, identifying key intermediary glycoprotein conformations coupled to membrane remodeling events. Using sub-tomogram averaging, we elucidate features of the low pH-exposed virion, nucleocapsid and full-length E1-glycoprotein’s post-fusion structure. Contrary to class-I fusion systems, CHIKV achieves membrane apposition by protrusion of extended E1-glycoprotein homotrimers into the target membrane. The fusion process also features a large hemifusion diaphragm that transitions to a wide pore for intact nucleocapsid delivery. Our analyses provide comprehensive ultrastructural insights into the class-II virus fusion system function and direct mechanistic characterization of the fundamental process of protein-mediated membrane fusion.

Date: 2022
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DOI: 10.1038/s41467-022-32431-9

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