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Title: Dynamic Changes during Acid-Induced Activation of Influenza Hemagglutinin

Abstract

Influenza hemagglutinin (HA) mediates virus attachment to host cells and fusion of the viral and endosomal membranes during entry. While high-resolution structures are available for the pre-fusion HA ectodomain and the post-fusion HA2 subunit, the sequence of conformational changes during HA activation has eluded structural characterization. In this paper, we apply hydrogen-deuterium exchange with mass spectrometry to examine changes in structural dynamics of the HA ectodomain at various stages of activation, and compare the soluble ectodomain with intact HA on virions. At pH conditions approaching activation (pH 6.0–5.5) HA exhibits increased dynamics at the fusion peptide and neighboring regions, while the interface between receptor binding subunits (HA1) becomes stabilized. In contrast to many activation models, these data suggest that HA responds to endosomal acidification by releasing the fusion peptide prior to HA1 uncaging and the spring-loaded refolding of HA2. Finally, this staged process may facilitate efficient HA-mediated fusion.

Authors:
; ; ;
Publication Date:
Research Org.:
Univ. of Washington, Seattle, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1246554
Alternate Identifier(s):
OSTI ID: 1347217
Grant/Contract Number:  
T32-GM007750; F32-GM097805; R00-GM080352; R01-GM099989; P41-GM103393; P41-RR001209
Resource Type:
Published Article
Journal Name:
Structure
Additional Journal Information:
Journal Name: Structure Journal Volume: 23 Journal Issue: 4; Journal ID: ISSN 0969-2126
Publisher:
Elsevier
Country of Publication:
United Kingdom
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Garcia, Natalie K., Guttman, Miklos, Ebner, Jamie L., and Lee, Kelly K. Dynamic Changes during Acid-Induced Activation of Influenza Hemagglutinin. United Kingdom: N. p., 2015. Web. doi:10.1016/j.str.2015.02.006.
Garcia, Natalie K., Guttman, Miklos, Ebner, Jamie L., & Lee, Kelly K. Dynamic Changes during Acid-Induced Activation of Influenza Hemagglutinin. United Kingdom. https://doi.org/10.1016/j.str.2015.02.006
Garcia, Natalie K., Guttman, Miklos, Ebner, Jamie L., and Lee, Kelly K. Wed . "Dynamic Changes during Acid-Induced Activation of Influenza Hemagglutinin". United Kingdom. https://doi.org/10.1016/j.str.2015.02.006.
@article{osti_1246554,
title = {Dynamic Changes during Acid-Induced Activation of Influenza Hemagglutinin},
author = {Garcia, Natalie K. and Guttman, Miklos and Ebner, Jamie L. and Lee, Kelly K.},
abstractNote = {Influenza hemagglutinin (HA) mediates virus attachment to host cells and fusion of the viral and endosomal membranes during entry. While high-resolution structures are available for the pre-fusion HA ectodomain and the post-fusion HA2 subunit, the sequence of conformational changes during HA activation has eluded structural characterization. In this paper, we apply hydrogen-deuterium exchange with mass spectrometry to examine changes in structural dynamics of the HA ectodomain at various stages of activation, and compare the soluble ectodomain with intact HA on virions. At pH conditions approaching activation (pH 6.0–5.5) HA exhibits increased dynamics at the fusion peptide and neighboring regions, while the interface between receptor binding subunits (HA1) becomes stabilized. In contrast to many activation models, these data suggest that HA responds to endosomal acidification by releasing the fusion peptide prior to HA1 uncaging and the spring-loaded refolding of HA2. Finally, this staged process may facilitate efficient HA-mediated fusion.},
doi = {10.1016/j.str.2015.02.006},
journal = {Structure},
number = 4,
volume = 23,
place = {United Kingdom},
year = {Wed Apr 01 00:00:00 EDT 2015},
month = {Wed Apr 01 00:00:00 EDT 2015}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1016/j.str.2015.02.006

Citation Metrics:
Cited by: 49 works
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Works referencing / citing this record:

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