Monday, March 11, 2013

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.

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