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}
}
https://doi.org/10.1016/j.str.2015.02.006
Web of Science
Works referencing / citing this record:
Bridging protein structure, dynamics, and function using hydrogen/deuterium‐exchange mass spectrometry
journal, April 2020
- Hodge, Edgar A.; Benhaim, Mark A.; Lee, Kelly K.
- Protein Science, Vol. 29, Issue 4
Fusion of Enveloped Viruses in Endosomes: Virus Fusion in Endosomes
journal, April 2016
- White, Judith M.; Whittaker, Gary R.
- Traffic, Vol. 17, Issue 6
Visualization and Sequencing of Membrane Remodeling Leading to Influenza Virus Fusion
journal, May 2016
- Gui, Long; Ebner, Jamie L.; Mileant, Alexander
- Journal of Virology, Vol. 90, Issue 15
Dissection of Epitope-Specific Mechanisms of Neutralization of Influenza Virus by Intact IgG and Fab Fragments
journal, December 2017
- Williams, James A.; Gui, Long; Hom, Nancy
- Journal of Virology, Vol. 92, Issue 6
Tracking Higher Order Protein Structure by Hydrogen-Deuterium Exchange Mass Spectrometry
journal, February 2019
- Benhaim, Mark; Lee, Kelly K.; Guttman, Miklos
- Protein & Peptide Letters, Vol. 26, Issue 1
Protein profiling and pseudo-parallel reaction monitoring to monitor a fusion-associated conformational change in hemagglutinin
journal, June 2019
- Nguyen, Khanh K.; Thurmond, Stephanie; Hai, Rong
- Analytical and Bioanalytical Chemistry, Vol. 411, Issue 19
Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site
journal, June 2017
- Strauch, Eva-Maria; Bernard, Steffen M.; La, David
- Nature Biotechnology, Vol. 35, Issue 7
Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies
journal, August 2019
- Adachi, Yu; Tonouchi, Keisuke; Nithichanon, Arnone
- Nature Communications, Vol. 10, Issue 1
Epitope mapping of diverse influenza Hemagglutinin drug candidates using HDX-MS
journal, March 2019
- Puchades, Cristina; Kűkrer, Başak; Diefenbach, Otto
- Scientific Reports, Vol. 9, Issue 1
Conformational Stability of the Hemagglutinin of H5N1 Influenza A Viruses Influences Susceptibility to Broadly Neutralizing Stem Antibodies
journal, March 2018
- Wang, Wei; Song, Hyo Sook; Keller, Paul W.
- Journal of Virology, Vol. 92, Issue 12
Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains
journal, February 2019
- Turner, Hannah L.; Pallesen, Jesper; Lang, Shanshan
- PLOS Biology, Vol. 17, Issue 2
Probing Structural Variation and Dynamics in the HIV-1 Env Fusion Glycoprotein
journal, April 2018
- Munro, James B.; Lee, Kelly K.
- Current HIV Research, Vol. 16, Issue 1
Dynamic Viral Glycoprotein Machines: Approaches for Probing Transient States That Drive Membrane Fusion
journal, January 2016
- Garcia, Natalie; Lee, Kelly
- Viruses, Vol. 8, Issue 1