Cell Invader: Dengue Virus Envelope Protein

The Dengue Virus Envelope Protein is a glycoprotein that shows how huge conformational shifts can be brought about by environmental changes in pH which lead to amazing functional significance. The glycoprotein forms a capsule around the lipid membrane of the virus with 180 copies of the protein that are anchored to the lipid membrane of the virus (1). 

GLYCOPROTEIN CAPSULE
http://www.virology.wisc.edu/virusworld/PS10/dng_dengue_virus_vmd.jpg

When forming a capsid the protein is associated as dimers. Once the virus capsid is taken up into a target cell via endocytosis things begin to get interesting. Endosomes utilize pH pumps to maintain a lower pH than the cytosol. This drop in pH inside the endosome causes the protein to undergo a large conformational shift (39 angstroms) (2) breaking the association of the dimers and leading to the formation of trimers. These trimers form spikes on the surface of the virus lipid membrane that have hydrophobic tips. These tips also known as fusion loops can insert into the target membrane of the endosome. The protein then undergoes a further conformatinal change in which the N and C termini are drawn together. This serves to make the protein fold in on itself and rotates the entire trimer 90 degrees in relation to the membranes. This draws the two membranes together allowing them to fuse and create a lipidic fusion pore through which the virus can dump its RNA into the cytosol of the target cell.

MEMBRANE FUSION PROCESS

Modis, Yorgo, Steven Ogata, David Clements, and Stephen Harrison. "Structure of the dengue virus envelope protein after membrane fusion." Nature 427 (2004): 313-19 

DENGUE VIRUS ANIMATION

Single Protein
Image made in PyMol from PDB File 1OK8

Protein Dimer in Membrane State
Image made in Pymol from PDB File 3J27

Protein Trimer Ready for Fusion
http://www.rcsb.org/pdb/101/motm.do?momID=103

Resources
1. http://www.rcsb.org/pdb/101/motm.do?momID=103 (PDM Molecule of the Month)

2. Modis, Yorgo, Steven Ogata, David Clements, and Stephen Harrison. "Structure of the dengue virus envelope protein after membrane fusion." Nature 427 (2004): 313-19

Literature Background on Dengue Virus Envelope Protein

The dengue virus envelope protein exists in two conformations. The conformational shift is stimulated by a change in pH. At pH >7 it exists as a dimer. When pH<7 the three domains of the protein shift , moving the C terminus a full 39 angstroms and causing the protein to associate into trimers. These conformational changes take it from providing a flat membrane surface in its high pH conformation to creating trimer “spikes” in its second conformation. These spikes are used to puncture endosomes and allow entrance of the virus into the cell.

Modis, Yorgo, Steven Ogata, David Clements, and Stephen Harrison. "Structure of the dengue virus envelope protein after membrane fusion" Nature 427 (2004): 313-19

The dengue virus is a flavivirus which is an insect-borne virus. Flaviviruses fuse to membranes via E proteins which are the primary external protein of the virion. The dengue virus envelope protein associates into a trimer in low pH environments. This trimer has a hydrophobic tip the inserts itself into the outer leaflet of the target membrane bilayer. The protein then undergoes more rearrangements that bring the membrane of the virus and the membrane of the target cell together to allow fusion of the membranes and release of the virus into the cytosol.

Schmidt, Aaron G., Priscilla L. Yang, and Stephen C. Harrison. "Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate" PLoS Pathogens 6.4 (2010): 1-11.

The conformational change of the dengue virus envelope protein is initiated by cleavage of the dimer associations. This occurs at low pH (5.0-6.0). the conformational change is reversible. The fusion of the protein with the target membrane occurs once prM (a peptide blocking the hydrophobic tip used for initial membrane fusion/anchoring) is cleaved from the trimers.

Yu, I-mei, Wei Zhang, Heather Holdaway, Long Li, and Victor Kostyuchenko. "Structure of the immature dengue virus at low pH primes proteolytic maturation" Science 319 (2008): 1834-37.

A Quick Look at Dengue Virus Envelope Protein