Cellular mRNA triggers structural transformation of Ebola virus matrix protein VP40 to its essential regulatory form

Cell Rep. 2021 Apr 13;35(2):108986. doi: 10.1016/j.celrep.2021.108986.


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.

Keywords: 3′ UTR; Ebola virus; VP40; crystal structure; deep sequencing; ebolavirus; mRNA; matrix protein; native mass spectrometry; transformer protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions*
  • Binding Sites
  • Crystallography, X-Ray
  • Ebolavirus / genetics*
  • Ebolavirus / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Guanine / chemistry*
  • Guanine / metabolism
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Models, Molecular
  • Nucleoproteins / chemistry*
  • Nucleoproteins / genetics
  • Nucleoproteins / metabolism
  • Nucleotide Motifs
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Viral Core Proteins / chemistry*
  • Viral Core Proteins / genetics
  • Viral Core Proteins / metabolism
  • Virus Assembly / genetics
  • Virus Release / genetics


  • 3' Untranslated Regions
  • Nucleoproteins
  • Recombinant Proteins
  • Viral Core Proteins
  • nucleoprotein VP40, Ebola virus
  • Guanine