Cellular mRNA triggers structural transformation of Ebola virus matrix protein VP40 to its essential regulatory form
Sara Landeras-Bueno,
Hal Wasserman,
Glenn Oliveira,
Zachary L. VanAernum,
Florian Busch,
Zhe Li Salie,
Vicki H. Wysocki,
Kristian Andersen,
Erica Ollmann Saphire
Affiliations
Sara Landeras-Bueno
La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Hal Wasserman
La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Glenn Oliveira
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Zachary L. VanAernum
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA; Resource for Native Mass Spectrometry Guided Structural Biology, The Ohio State University, Columbus, OH 43210, USA
Florian Busch
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA; Resource for Native Mass Spectrometry Guided Structural Biology, The Ohio State University, Columbus, OH 43210, USA
Zhe Li Salie
La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Vicki H. Wysocki
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA; Resource for Native Mass Spectrometry Guided Structural Biology, The Ohio State University, Columbus, OH 43210, USA
Kristian Andersen
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Erica Ollmann Saphire
La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Corresponding author
Summary: 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 3′ 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 Å 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.
