A toggle switch controls the low pH-triggered rearrangement and maturation of the dengue virus envelope proteins.
Immature dengue virus particles undergo a dramatic conformational change upon exposure to the acidic environment of the late secretory pathway. The interactions of the E fusion proteins and prM chaperone proteins on the virus envelope are reorganized to permit prM processing by a host protease, furin, thus priming virus for fusion and infection. Here we identify a pH-dependent toggle switch that controls this key conformational change during virus maturation. Our data show that the M region of prM interacts with E at neutral pH but is released at acidic pH, while the pr region interacts with E at acidic pH but is released at neutral pH. Alanine substitution of the conserved residue H98 in prM disrupts the switch by inhibiting dissociation of M from E at low pH, resulting in impaired prM processing and decreased virus infectivity. Thus, release of M-E interaction at low pH promotes formation of a furin-accessible intermediate.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Aihua
A
Zheng
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Fei
F
Yuan
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Lara M
LM
Kleinfelter
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Margaret
M
Kielian
D003716:Dengue Virus / Q000378:metabolism*; D045683:Furin / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D014759:Viral Envelope Proteins / Q000378:metabolism*
D014759:Viral Envelope Proteins; D045683:Furin