Structure of the immature dengue virus at low pH primes proteolytic maturation.
Intracellular cleavage of immature flaviviruses is a critical step in assembly that generates the membrane fusion potential of the E glycoprotein. With cryo-electron microscopy we show that the immature dengue particles undergo a reversible conformational change at low pH that renders them accessible to furin cleavage. At a pH of 6.0, the E proteins are arranged in a herringbone pattern with the pr peptides docked onto the fusion loops, a configuration similar to that of the mature virion. After cleavage, the dissociation of pr is pH-dependent, suggesting that in the acidic environment of the trans-Golgi network pr is retained on the virion to prevent membrane fusion. These results suggest a mechanism by which flaviviruses are processed and stabilized in the host cell secretory pathway.
Yu
I-Mei
IM
Department of Biological Sciences, 915 West State Street, Purdue University, West Lafayette, IN 47907-2054, USA.
Zhang
Wei
W
Holdaway
Heather A
HA
Li
Long
L
Kostyuchenko
Victor A
VA
Chipman
Paul R
PR
Kuhn
Richard J
RJ
Rossmann
Michael G
MG
Chen
Jue
J
D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D003716:Dengue Virus / Q000737:chemistry* / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure*; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000821:virology; D045683:Furin / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007091:Image Processing, Computer-Assisted; D008561:Membrane Fusion; D011487:Protein Conformation; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D014771:Virion / Q000378:metabolism / Q000648:ultrastructure; D021601:trans-Golgi Network / Q000378:metabolism / Q000821:virology
C051821:E-glycoprotein, Dengue virus type 2; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; D014763:Viral Matrix Proteins; D045683:Furin