41159
2016
2019
eng
32
676
postprint
1
2019-03-07
2019-03-07
--
Mechanistic insight into bunyavirus-induced membrane fusion from structure-function analyses of the hantavirus envelope glycoprotein Gc
Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic beta-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha-and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single "fusion loop". We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal "tail" that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens.
Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
10.25932/publishup-41159
urn:nbn:de:kobv:517-opus4-411599
1866-8372
online registration
PLoS Pathogens 12 (2016) 10, Art. e1005813 DOI 10.1371/journal.ppat.1005813
e1005813
false
true
CC-BY - Namensnennung 4.0 International
Pablo Guardado-Calvo
Eduardo A. Bignon
Eva Stettner
Scott Allen Jeffers
Jimena Pérez-Vargas
Gerard Pehau-Arnaudet
M. Alejandra Tortorici
Jean- Luc Jestin
Patrick England
Nicole D. Tischler
Félix A. Rey
Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
676
eng
uncontrolled
Semliki-forest-virus
eng
uncontrolled
Borne encephalitis-virus
eng
uncontrolled
N-linked glycosylation
eng
uncontrolled
human dendritic cells
eng
uncontrolled
Valley fever virus
eng
uncontrolled
Hantaan-virus
eng
uncontrolled
Hemorrhagic-fever
eng
uncontrolled
crystal-structure
eng
uncontrolled
electron crytomography
eng
uncontrolled
pulmonary syndrome
Medizin und Gesundheit
open_access
Mathematisch-Naturwissenschaftliche Fakultät
Referiert
Open Access
Public Library of Science (PLOS)
Universität Potsdam
https://publishup.uni-potsdam.de/files/41159/pmnr676.pdf
44888
2016
2016
eng
153
166
32
12
article
PLoS
San Fransisco
1
--
--
--
Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic beta-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha-and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single "fusion loop". We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal "tail" that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens.
PLoS Pathogens
10.1371/journal.ppat.1005813
27783711
1553-7366
1553-7374
wos2016:2019
e1005813
WOS:000387666900002
Tischler, ND (reprint author), Fdn Ciencia & Vida, Mol Virol Lab, Santiago, Chile., ntischler@cienciavida.org; felix.rey@pasteur.fr
Infect-ERA IMI European network, program "HantaHunt"; "Integrative Biology of Emerging Infectious Diseases" Labex (Laboratoire "Virus Entry" [FP7-PEOPLE-2007-1-1-ITN]; FONDECYT [1140050]; CONICYT (Chile)
importub
2020-03-22T13:56:02+00:00
filename=package.tar
4c0ceb4affd6948b78ff76aaa68f055c
Pablo Guardado-Calvo
Eduardo A. Bignon
Eva Stettner
Scott Allen Jeffers
Jimena Perez-Vargas
Gerard Pehau-Arnaudet
M. Alejandra Tortoric
Jean-Luc Jestin
Patrick England
Nicole D. Tischler
Felix A. Rey
Institut für Biochemie und Biologie
Referiert
Import