The Stem Region of Premembrane Protein Plays an Important Role in the Virus Surface Protein Rearrangement During Dengue Maturation

J Biol Chem. 2012 Nov 23;287(48):40525-34. doi: 10.1074/jbc.M112.384446. Epub 2012 Oct 3.

Abstract

Background: Dengue virus surface proteins, envelope (E) and pre-membrane (prM), undergo rearrangement during the maturation process at acidic condition.

Results: prM-stem region binds tighter to both E protein and lipid membrane when environment becomes acidic.

Conclusion: At acidic condition, E proteins are attracted to the membrane-associated prM-stem.

Significance: prM-stem region induces virus structural changes during maturation. Newly assembled dengue viruses (DENV) undergo maturation to become infectious particles. The maturation process involves major rearrangement of virus surface premembrane (prM) and envelope (E) proteins. The prM-E complexes on immature viruses are first assembled as trimeric spikes in the neutral pH environment of the endoplasmic reticulum. When the virus is transported to the low pH environment of the exosomes, these spikes rearrange into dimeric structures, which lie parallel to the virus lipid envelope. The proteins involved in driving this process are unknown. Previous cryoelectron microscopy studies of the mature DENV showed that the prM-stem region (residues 111-131) is membrane-associated and may interact with the E proteins. Here we investigated the prM-stem region in modulating the virus maturation process. The binding of the prM-stem region to the E protein was shown to increase significantly at low pH compared with neutral pH in ELISAs and surface plasmon resonance studies. In addition, the affinity of the prM-stem region for the liposome, as measured by fluorescence correlation spectroscopy, was also increased when pH is lowered. These results suggest that the prM-stem region forms a tight association with the virus membrane and attracts the associated E protein in the low pH environment of exosomes. This will lead to the surface protein rearrangement observed during maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Dengue / virology*
  • Dengue Virus / chemistry
  • Dengue Virus / genetics
  • Dengue Virus / physiology*
  • Humans
  • Molecular Sequence Data
  • Sequence Alignment
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism*
  • Virus Assembly*

Substances

  • Viral Envelope Proteins