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Cryo-EM structure of the mature dengue virus at 3.5-Å resolution
Xiaokang Zhang1, Peng Ge, Xuekui Yu
1Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles-UCLA, Los Angeles, California, USA.
Abstract:
Regulated by pH, membrane-anchored proteins E and M function during dengue virus maturation and membrane fusion. Our atomic model of the whole virion from cryo-electron microscopy at 3.5-Å resolution reveals that in the mature virus at neutral extracellular pH, the N-terminal 20-amino-acid segment of M (involving three pH-sensing histidines) latches and thereby prevents spring-loaded E fusion protein from prematurely exposing its fusion peptide. This M latch is fastened at an earlier stage, during maturation at acidic pH in the trans-Golgi network. At a later stage, to initiate infection in response to acidic pH in the late endosome, M releases the latch and exposes the fusion peptide. Thus, M serves as a multistep chaperone of E to control the conformational changes accompanying maturation and infection. These pH-sensitive interactions could serve as targets for drug discovery.
Insights
The dengue virus M protein acts as a chaperone, controlling the E protein
Area of Science:
- Structural biology
- Virology
- Biochemistry
Background:
- Dengue virus maturation and membrane fusion are regulated by pH-dependent interactions of membrane proteins E and M.
- Understanding the molecular mechanisms of these proteins is crucial for developing antiviral strategies.
Purpose of the Study:
- To elucidate the atomic structure of the dengue virion and the role of protein M in regulating protein E.
- To investigate the pH-sensitive conformational changes of proteins E and M during virus maturation and infection.
Main Methods:
- Cryo-electron microscopy (cryo-EM) at 3.5-Å resolution to determine the atomic model of the whole dengue virion.
- Analysis of pH-sensitive interactions between proteins M and E, focusing on the N-terminal segment of M.
Main Results:
- The M protein's N-terminal segment acts as a latch, preventing premature exposure of the E protein's fusion peptide at neutral pH.
- This M latch is established during maturation in the acidic trans-Golgi network and released in the acidic late endosome.
- Protein M functions as a multistep chaperone, controlling E protein conformational changes essential for maturation and infection.
Conclusions:
- The M protein's pH-sensitive latch mechanism is critical for regulating dengue virus infectivity.
- These pH-sensitive interactions represent potential targets for novel antiviral drug discovery.
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