scholarly journals Receptor binding may directly activate the fusion machinery in coronavirus spike glycoproteins

2021 ◽  
Author(s):  
Yuzhang Wang ◽  
Lucy Fallon ◽  
Lauren Raguette ◽  
Stephanie Budhan ◽  
Kellon Belfon ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Rna Virus ◽  
X Ray ◽  
Cognate Receptor ◽  
Binding Domains ◽  
Membrane Fusion Proteins ◽  
Viral Membrane Fusion

SARS-CoV-2, the causative agent of the COVID-19 pandemic, is an enveloped RNA virus. Trimeric spike glycoproteins extend outward from the virion; these class I viral membrane fusion proteins mediate entry of the virus into a host cell and are the dominant antigen for immune response. Cryo-EM studies have generated a large number of structures for the spike either alone, or bound to the cognate receptor ACE2 or antibodies, with the three receptor binding domains (RBDs) seen closed, open, or in various combinations. Binding to ACE2 requires an open RBD, and is believed to trigger the series of dramatic conformational changes in the spike that lead to the shedding of the S1 subunit and transition of the spring-loaded S2 subunit to the experimentally observed post-fusion structure. The steps following ACE2 binding are poorly understood despite extensive characterization of the spike through X-ray, cryo-EM, and computation. Here, we use all-atom simulations, guided by analysis of 81 existing experimental structures, to develop a model for the structural and energetic coupling that connects receptor binding to activation of the membrane fusion machinery.

scholarly journals Conformational changes in the Ebola virus membrane fusion machine induced by pH, Ca2+, and receptor binding

PLoS Biology ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. e3000626 ◽  
Author(s):  
Dibyendu Kumar Das ◽  
Uriel Bulow ◽  
William E. Diehl ◽  
Natasha D. Durham ◽  
Fernando Senjobe ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Ebola Virus

scholarly journals Influenza Hemagglutinin (HA) Stem Region Mutations That Stabilize or Destabilize the Structure of Multiple HA Subtypes

2015 ◽  
Vol 89 (8) ◽  
pp. 4504-4516 ◽  
Author(s):  
Lauren Byrd-Leotis ◽  
Summer E. Galloway ◽  
Evangeline Agbogu ◽  
David A. Steinhauer
Keyword(s):  
Membrane Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Influenza A ◽  
Mutational Analysis ◽  
Host Cells ◽  
Influenza A Viruses ◽  
Pathogenic Potential ◽  
Additional Tool ◽  
Improved Stability

ABSTRACTInfluenza A viruses enter host cells through endosomes, where acidification induces irreversible conformational changes of the viral hemagglutinin (HA) that drive the membrane fusion process. The prefusion conformation of the HA is metastable, and the pH of fusion can vary significantly among HA strains and subtypes. Furthermore, an accumulating body of evidence implicates HA stability properties as partial determinants of influenza host range, transmission phenotype, and pathogenic potential. Although previous studies have identified HA mutations that can affect HA stability, these have been limited to a small selection of HA strains and subtypes. Here we report a mutational analysis of HA stability utilizing a panel of expressed HAs representing a broad range of HA subtypes and strains, including avian representatives across the phylogenetic spectrum and several human strains. We focused on two highly conserved residues in the HA stem region: HA2 position 58, located at the membrane distal tip of the short helix of the hairpin loop structure, and HA2 position 112, located in the long helix in proximity to the fusion peptide. We demonstrate that a K58I mutation confers an acid-stable phenotype for nearly all HAs examined, whereas a D112G mutation consistently leads to elevated fusion pH. The results enhance our understanding of HA stability across multiple subtypes and provide an additional tool for risk assessment for circulating strains that may have other hallmarks of human adaptation. Furthermore, the K58I mutants, in particular, may be of interest for potential use in the development of vaccines with improved stability profiles.IMPORTANCEThe influenza A hemagglutinin glycoprotein (HA) mediates the receptor binding and membrane fusion functions that are essential for virus entry into host cells. While receptor binding has long been recognized for its role in host species specificity and transmission, membrane fusion and associated properties of HA stability have only recently been appreciated as potential determinants. We show here that mutations can be introduced at highly conserved positions to stabilize or destabilize the HA structure of multiple HA subtypes, expanding our knowledge base for this important phenotype. The practical implications of these findings extend to the field of vaccine design, since the HA mutations characterized here could potentially be utilized across a broad spectrum of influenza virus subtypes to improve the stability of vaccine strains or components.

scholarly journals Conformational States of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Ectodomain

2006 ◽  
Vol 80 (14) ◽  
pp. 6794-6800 ◽  
Author(s):  
Fang Li ◽  
Marcelo Berardi ◽  
Wenhui Li ◽  
Michael Farzan ◽  
Philip R. Dormitzer ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Membrane Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Viral Entry ◽  
Protein S ◽  
Spike Protein ◽  
Fusion Peptides ◽  
Conformational States ◽  
Protease Cleavage

ABSTRACT The severe acute respiratory syndrome coronavirus enters cells through the activities of a spike protein (S) which has receptor-binding (S1) and membrane fusion (S2) regions. We have characterized four sequential states of a purified recombinant S ectodomain (S-e) comprising S1 and the ectodomain of S2. They are S-e monomers, uncleaved S-e trimers, cleaved S-e trimers, and dissociated S1 monomers and S2 trimer rosettes. Lowered pH induces an irreversible transition from flexible, L-shaped S-e monomers to clove-shaped trimers. Protease cleavage of the trimer occurs at the S1-S2 boundary; an ensuing S1 dissociation leads to a major rearrangement of the trimeric S2 and to formation of rosettes likely to represent clusters of elongated, postfusion trimers of S2 associated through their fusion peptides. The states and transitions of S suggest conformational changes that mediate viral entry into cells.

scholarly journals Class II Contact-Dependent growth Inhibition (CDI) systems allow for broad-range cross-species toxin delivery

2019 ◽  
Author(s):  
Petra Virtanen ◽  
Marcus Wäneskog ◽  
Sanna Koskiniemi
Keyword(s):  
Growth Inhibition ◽  
Receptor Binding ◽  
Class Ii ◽  
Receptor Protein ◽  
Bacterial Populations ◽  
Cognate Receptor ◽  
Binding Domains ◽  
Dependent Growth ◽  
Species Specific ◽  
Contact Dependent Growth Inhibition

AbstractContact-dependent growth inhibition (CDI) allows bacteria to recognize kin cells in mixed bacterial populations. In Escherichia coli, CDI mediated effector delivery has been shown to be species-specific, with a preference for the own strain over others. This specificity is achieved through an interaction between a receptor-binding domain in the CdiA protein and its cognate receptor protein on the target cell. But how conserved this specificity is has not previously been investigated in detail. Here we show that three different class II CdiA receptor-binding domains and their Enterobacter cloacae analog are highly promiscuous, allowing for efficient effector delivery into several different Enterobacteriaceae species, including Escherichia, Enterobacter, Klebsiella and Salmonella spp. In addition, although we observe a preference for some receptors over others, this did not limit cross-species effector delivery, suggesting that class II CdiA proteins can allow for broad-range and cross-species growth inhibition in mixed bacterial populations.

scholarly journals Fusogenic Reoviruses and Their Fusion-Associated Small Transmembrane (FAST) Proteins

2019 ◽  
Vol 6 (1) ◽  
pp. 341-363 ◽  
Author(s):  
Roy Duncan
Keyword(s):  
Membrane Fusion ◽  
Fusion Proteins ◽  
Syncytium Formation ◽  
Nonstructural Proteins ◽  
Enveloped Virus ◽  
Fast Proteins ◽  
Nonenveloped Virus ◽  
Functional Features ◽  
Membrane Fusion Proteins ◽  
Viral Membrane Fusion

With no limiting membrane surrounding virions, nonenveloped viruses have no need for membrane fusion to gain access to intracellular replication compartments. Consequently, nonenveloped viruses do not encode membrane fusion proteins. The only exception to this dogma is the fusogenic reoviruses that encode fusion-associated small transmembrane (FAST) proteins that induce syncytium formation. FAST proteins are the smallest viral membrane fusion proteins and, unlike their enveloped virus counterparts, are nonstructural proteins that evolved specifically to induce cell-to-cell, not virus-cell, membrane fusion. This distinct evolutionary imperative is reflected in structural and functional features that distinguish this singular family of viral fusogens from all other protein fusogens. These rudimentary fusogens comprise specific combinations of different membrane effector motifs assembled into small, modular membrane fusogens. FAST proteins offer a minimalist model to better understand the ubiquitous process of protein-mediated membrane fusion and to reveal novel mechanisms of nonenveloped virus dissemination that contribute to virulence.

scholarly journals Nipah Virus Attachment Glycoprotein Stalk C-Terminal Region Links Receptor Binding to Fusion Triggering

2014 ◽  
Vol 89 (3) ◽  
pp. 1838-1850 ◽  
Author(s):  
Qian Liu ◽  
Birgit Bradel-Tretheway ◽  
Abrrey I. Monreal ◽  
Jonel P. Saludes ◽  
Xiaonan Lu ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Cell Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Viral Entry ◽  
Nipah Virus ◽  
Cell Receptor ◽  
Terminal Region ◽  
Content Type ◽  
Cell Cell

ABSTRACTMembrane fusion is essential for paramyxovirus entry into target cells and for the cell-cell fusion (syncytia) that results from many paramyxoviral infections. The concerted efforts of two membrane-integral viral proteins, the attachment (HN, H, or G) and fusion (F) glycoproteins, mediate membrane fusion. The emergent Nipah virus (NiV) is a highly pathogenic and deadly zoonotic paramyxovirus. We recently reported that upon cell receptor ephrinB2 or ephrinB3 binding, at least two conformational changes occur in the NiV-G head, followed by one in the NiV-G stalk, that subsequently result in F triggering and F execution of membrane fusion. However, the domains and residues in NiV-G that trigger F and the specific events that link receptor binding to F triggering are unknown. In the present study, we identified a NiV-G stalk C-terminal region (amino acids 159 to 163) that is important for multiple G functions, including G tetramerization, conformational integrity, G-F interactions, receptor-induced conformational changes in G, and F triggering. On the basis of these results, we propose that this NiV-G region serves as an important structural and functional linker between the NiV-G head and the rest of the stalk and is critical in propagating the F-triggering signal via specific conformational changes that open a concealed F-triggering domain(s) in the G stalk. These findings broaden our understanding of the mechanism(s) of receptor-induced paramyxovirus F triggering during viral entry and cell-cell fusion.IMPORTANCEThe emergent deadly viruses Nipah virus (NiV) and Hendra virus belong to theHenipavirusgenus in theParamyxoviridaefamily. NiV infections target endothelial cells and neurons and, in humans, result in 40 to 75% mortality rates. The broad tropism of the henipaviruses and the unavailability of therapeutics threaten the health of humans and livestock. Viral entry into host cells is the first step of henipavirus infections, which ultimately cause syncytium formation. After attaching to the host cell receptor, henipaviruses enter the target cell via direct viral-cell membrane fusion mediated by two membrane glycoproteins: the attachment protein (G) and the fusion protein (F). In this study, we identified and characterized a region in the NiV-G stalk C-terminal domain that links receptor binding to fusion triggering via several important glycoprotein functions. These findings advance our understanding of the membrane fusion-triggering mechanism(s) of the henipaviruses and the paramyxoviruses.

Solution and solid-state characterization of a dicopper receptor for large substrates

2002 ◽  
Vol 80 (5) ◽  
pp. 496-498 ◽  
Author(s):  
Greg JE Davidson ◽  
Andrew J Baer ◽  
Adrien P Côté ◽  
Nicholas J Taylor ◽  
Garry S Hanan ◽  
...  
Keyword(s):  
Metal Binding ◽  
Central Cavity ◽  
X Ray ◽  
X Ray Crystallography ◽  
Binding Domains ◽  
Rigid Spacer ◽  
Complex Coordination ◽  
Solid State Characterization ◽  
Large Central Cavity

Ligand 2 contains two metal-binding domains separated by a rigid spacer and assembles into a dicopper receptor with a large central cavity with no evidence of catenation.Key words: copper complex, coordination, X-ray crystallography, molecular recognition.

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