Journal
CELL REPORTS
Volume 35, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.108986
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Funding
- NIH [P41 GM128577]
- DOE Office of Science [DE-AC02-06CH11357]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41 GM103393]
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The study reveals that VP40 forms distinct structures associated with different functions in the Ebola virus life cycle, with suitable nucleic acid triggering a dynamic transformation from dimeric to octameric ring VP40. The deep sequencing shows a binding preference of the VP40 ring for the 30 untranslated region of cellular mRNA with a guanine- and adenine-rich binding motif, providing insights into potential therapeutic inhibition opportunities.
The Ebola virus matrix protein VP40 forms distinct structures linked to distinct functions in the virus life cycle. Dimeric VP40 is a structural protein associated with virus assembly, while octameric, ring-shaped VP40 is associated with transcriptional control. In this study, we show that suitable nucleic acid is sufficient to trigger a dynamic transformation of VP40 dimer into the octameric ring. Deep sequencing reveals a binding preference of the VP40 ring for the 30 untranslated region of cellular mRNA and a guanine- and adenine-rich binding motif. Complementary analyses of the nucleic-acid-induced VP40 ring by native mass spectrometry, electron microscopy, and X-ray crystal structures at 1.8 and 1.4 angstrom resolution reveal the stoichiometry of RNA binding, as well as an interface involving a key guanine nucleotide. The host factor-induced structural transformation of protein structure in response to specific RNA triggers in the Ebola virus life cycle presents unique opportunities for therapeutic inhibition.
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