scholarly journals Condensation of the influenza viral fusion peptide alters membrane structure and water permeability

2021 ◽  
Author(s):  
Sourav Haldar ◽  
Amy Rice ◽  
Eric Wang ◽  
Paul S. Blank ◽  
Sergey A. Akimov ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Water Permeability ◽  
Membrane Structure ◽  
Pore Formation ◽  
Electron Tomography ◽  
Cellular Membrane ◽  
Fusion Peptide ◽  
Lipid Monolayer ◽  
Viral Fusion ◽  
Dynamics Simulations

To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out beyond a forest of viral spikes to embed into the target cellular membrane. Here we report that isolated FP of influenza virus are membrane active by themselves generating pores in giant unilamellar vesicles and thus potentially explain both influenza virus' hemolytic activity and structure in cryo-electron tomography. Molecular dynamics simulations of asymmetric bilayers with different numbers of FP in one leaflet show substantial peptide clustering. At the center of this peptide condensate a profound change in the membrane structure results in thinning, higher water permeability, and curvature. In effect, a hybrid bilayer forms locally with one lipid monolayer and one peptide monolayer. Membrane elastic theory predicts that the energy landscape becomes favorable for spontaneous pore formation in this novel structure, consistent with the inhibition of pore formation by cholesterol observed experimentally.

scholarly journals Functional Analysis of the Putative Fusion Domain of the Baculovirus Envelope Fusion Protein F

2004 ◽  
Vol 78 (13) ◽  
pp. 6946-6954 ◽  
Author(s):  
Marcel Westenberg ◽  
Frank Veenman ◽  
Els C. Roode ◽  
Rob W. Goldbach ◽  
Just M. Vlak ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Conformational Changes ◽  
Cellular Membrane ◽  
Fusion Peptide ◽  
Single Amino Acid ◽  
Viral Infectivity ◽  
Viral Fusion ◽  
F Protein ◽  
Group I ◽  
N Terminus

ABSTRACT Group II nucleopolyhedroviruses (NPVs), e.g., Spodoptera exigua MNPV, lack a GP64-like protein that is present in group I NPVs but have an unrelated envelope fusion protein named F. In contrast to GP64, the F protein has to be activated by a posttranslational cleavage mechanism to become fusogenic. In several vertebrate viral fusion proteins, the cleavage activation generates a new N terminus which forms the so-called fusion peptide. This fusion peptide inserts in the cellular membrane, thereby facilitating apposition of the viral and cellular membrane upon sequential conformational changes of the fusion protein. A similar peptide has been identified in NPV F proteins at the N terminus of the large membrane-anchored subunit F1. The role of individual amino acids in this putative fusion peptide on viral infectivity and propagation was studied by mutagenesis. Mutant F proteins with single amino acid changes as well as an F protein with a deleted putative fusion peptide were introduced in gp64-null Autographa californica MNPV budded viruses (BVs). None of the mutations analyzed had an major effect on the processing and incorporation of F proteins in the envelope of BVs. Only two mutants, one with a substitution for a hydrophobic residue (F152R) and one with a deleted putative fusion peptide, were completely unable to rescue the gp64-null mutant. Several nonconservative substitutions for other hydrophobic residues and the conserved lysine residue had only an effect on viral infectivity. In contrast to what was expected from vertebrate virus fusion peptides, alanine substitutions for glycines did not show any effect.

scholarly journals Polymorphism and Interactions of a Viral Fusion Peptide in a Compressed Lipid Monolayer

1999 ◽  
Vol 76 (6) ◽  
pp. 3167-3175 ◽  
Author(s):  
Gerhard Schwarz ◽  
Susanne E. Taylor
Keyword(s):  
Fusion Peptide ◽  
Lipid Monolayer ◽  
Viral Fusion

scholarly journals New Insights into the Spring-Loaded Conformational Change of Influenza Virus Hemagglutinin

2002 ◽  
Vol 76 (9) ◽  
pp. 4456-4466 ◽  
Author(s):  
Jennifer A. Gruenke ◽  
R. Todd Armstrong ◽  
William W. Newcomb ◽  
Jay C. Brown ◽  
Judith M. White
Keyword(s):  
Influenza Virus ◽  
Conformational Change ◽  
Conformational Changes ◽  
Limited Proteolysis ◽  
Coiled Coil ◽  
Fusion Peptide ◽  
Wild Type ◽  
Influenza Virus Hemagglutinin ◽  
Target Membrane ◽  
Mutant Forms

ABSTRACT Influenza virus hemagglutinin undergoes a conformational change in which a loop-to-helix “spring-loaded” conformational change forms a coiled coil that positions the fusion peptide for interaction with the target bilayer. Previous work has shown that two proline mutations designed to disrupt this change disrupt fusion but did not determine the basis for the fusion defect. In this work, we made six additional mutants with single proline substitutions in the region that undergoes the spring-loaded conformational change and two additional mutants with double proline substitutions in this region. All double mutants were fusion inactive. We analyzed one double mutant, F63P/F70P, as an example. We observed that F63P/F70P undergoes key low-pH-induced conformational changes and binds tightly to target membranes. However, limited proteolysis and electron microscopy observations showed that the mutant forms a coiled coil that is only ∼50% the length of the wild type, suggesting that it is splayed in its N-terminal half. This work further supports the hypothesis that the spring-loaded conformational change is necessary for fusion. Our data also indicate that the spring-loaded conformational change has another role beyond presenting the fusion peptide to the target membrane.

scholarly journals Elucidating the structural features of ABCA1 in its heterogeneous membrane environment.

2021 ◽  
Author(s):  
Sunidhi S ◽  
Sukriti Sacher ◽  
Parth Garg ◽  
Arjun Ray
Keyword(s):  
Conformational Changes ◽  
Transmembrane Protein ◽  
Direct Interaction ◽  
Structural Features ◽  
Lipid Binding ◽  
Lipid Monolayer ◽  
Alternative Theory ◽  
Lipid Dynamics ◽  
Lipid Environment ◽  
Dynamics Simulations

ABCA1 plays an integral part in Reverse Cholesterol Transport (RCT) and is critical for maintaining lipid homeostasis. One theory of lipid efflux by the transporter (alternating access) proposes that ABCA1 harbors two different conformations that provide alternate access for lipid binding and release, leading to sequestration via a direct interaction between ABCA1 and its partner, ApoA1. The alternative theory (lateral access) proposes that ABCA1 obtains lipids laterally from the membrane to form a temporary extracellular reservoir containing an isolated pressurized lipid monolayer caused by the net accumulation of lipids in the exofacial leaflet. Recently, a full-length Cryo-EM structure of this 2,261-residue transmembrane protein showed its discreetly folded domains and conformations, as well as detected the presence of a tunnel enclosed within ECDs. While the tunnel was wide enough at the proximal end for accommodating passage of lipids, the distal end displayed substantial narrowing, making it inaccessible for ApoA1. Therefore, this structure was hypothesized to substantiate the lateral access theory, whereby ApoA1 obtained lipids from the proximal end. Utilizing long time-scale multiple replica atomistic molecular dynamics simulations (MDS), we simulated the structure in a heterogeneous lipid environment and found that along with several large conformational changes, the protein widens enough at the distal end of its ECD tunnel to now enable lipid accommodation. In this study we have characterized ABCA1 and the lipid dynamics along with the protein-lipid interactions in the heterogeneous environment, providing novel insights into understanding ABCA1 conformation at an atomistic level.

scholarly journals CryoEM and computer simulations reveal a novel kinase conformational switch in bacterial chemotaxis signaling

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
C Keith Cassidy ◽  
Benjamin A Himes ◽  
Frances J Alvarez ◽  
Jun Ma ◽  
Gongpu Zhao ◽  
...  
Keyword(s):  
Electron Tomography ◽  
Conformational Dynamics ◽  
Bacterial Chemotaxis ◽  
Adaptor Protein ◽  
Structural Description ◽  
Structural Constraints ◽  
The Core ◽  
Molecular Events ◽  
Density Map ◽  
Dynamics Simulations

Chemotactic responses in bacteria require large, highly ordered arrays of sensory proteins to mediate the signal transduction that ultimately controls cell motility. A mechanistic understanding of the molecular events underlying signaling, however, has been hampered by the lack of a high-resolution structural description of the extended array. Here, we report a novel reconstitution of the array, involving the receptor signaling domain, histidine kinase CheA, and adaptor protein CheW, as well as a density map of the core-signaling unit at 11.3 Å resolution, obtained by cryo-electron tomography and sub-tomogram averaging. Extracting key structural constraints from our density map, we computationally construct and refine an atomic model of the core array structure, exposing novel interfaces between the component proteins. Using all-atom molecular dynamics simulations, we further reveal a distinctive conformational change in CheA. Mutagenesis and chemical cross-linking experiments confirm the importance of the conformational dynamics of CheA for chemotactic function.

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