Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 20, Issue 1, Pages 105-U133Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2463
Keywords
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Funding
- US National Institutes of Health [GM071940]
- National Natural Science Foundation of China (NSFC) [30928003, 30725017]
- NSFC [30470085, 30870480]
- National Institutes of Health [1S10RR23057]
- California NanoSystems Institute at UCLA
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR023057] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM071940] Funding Source: NIH RePORTER
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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-angstrom 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.
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