455 research outputs found
The structure of Herpesvirus Fusion Glycoprotein B-Bilayer Complex reveals the protein-membrane and lateral protein-protein interaction
Glycoprotein B (gB) is a key component of the complex herpesvirus fusion machinery. We studied membrane interaction of two gB ectodomain forms and present an electron cryotomography structure of the gB-bilayer complex. The two forms differed in presence or absence of the membrane proximal region (MPR) but showed an overall similar trimeric shape. The presence of the MPR impeded interaction with liposomes. In contrast, the MPR-lacking form interacted efficiently with liposomes. Lateral interaction resulted in coat formation on the membranes. The structure revealed that interaction of gB with membranes was mediated by the fusion loops and limited to the outer membrane leaflet. The observed intrinsic propensity of gB to cluster on membranes indicates an additional role of gB in driving the fusion process forward beyond the transient fusion pore opening and subsequently leading to fusion pore expansion
The prefusion structure of herpes simplex virus glycoprotein B.
Cell entry of enveloped viruses requires specialized viral proteins that mediate fusion with the host membrane by substantial structural rearrangements from a metastable pre- to a stable postfusion conformation. This metastability renders the herpes simplex virus 1 (HSV-1) fusion glycoprotein B (gB) highly unstable such that it readily converts into the postfusion form, thereby precluding structural elucidation of the pharmacologically relevant prefusion conformation. By identification of conserved sequence signatures and molecular dynamics simulations, we devised a mutation that stabilized this form. Functionally locking gB allowed the structural determination of its membrane-embedded prefusion conformation at sub-nanometer resolution and enabled the unambiguous fit of all ectodomains. The resulting pseudo-atomic model reveals a notable conservation of conformational domain rearrangements during fusion between HSV-1 gB and the vesicular stomatitis virus glycoprotein G, despite their very distant phylogeny. In combination with our comparative sequence-structure analysis, these findings suggest common fusogenic domain rearrangements in all class III viral fusion proteins
Implications of a High-Mass Diphoton Resonance for Heavy Quark Searches
Heavy vector-like quarks coupled to a scalar will induce a coupling of
this scalar to gluons and possibly (if electrically charged) photons. The decay
of the heavy quark into , with being a Standard Model quark, provides,
if kinematically allowed, new channels for heavy quark searches. Inspired by
naturalness considerations, we consider the case of a vector-like partner of
the top quark. For illustration, we show that a singlet partner can be searched
for at the 13TeV LHC through its decay into a scalar resonance in the
final states, especially if the diphoton branching ratio of
the scalar is further enhanced by the contribution of non coloured
particles. We then show that conventional heavy quark searches are also
sensitive to this new decay mode, when decays hadronically, by slightly
tightening the current selection cuts. Finally, we comment about the
possibility of disentangling, by scrutinising appropriate kinematic
distributions, heavy quark decays to from other standard decay modes.Comment: 8 pages, 3 figures and 1 table; v3: typos fixed. Matches published
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Recommendations of the LHC Dark Matter Working Group: Comparing LHC searches for heavy mediators of dark matter production in visible and invisible decay channels
Weakly-coupled TeV-scale particles may mediate the interactions between
normal matter and dark matter. If so, the LHC would produce dark matter through
these mediators, leading to the familiar "mono-X" search signatures, but the
mediators would also produce signals without missing momentum via the same
vertices involved in their production. This document from the LHC Dark Matter
Working Group suggests how to compare searches for these two types of signals
in case of vector and axial-vector mediators, based on a workshop that took
place on September 19/20, 2016 and subsequent discussions. These suggestions
include how to extend the spin-1 mediated simplified models already in
widespread use to include lepton couplings. This document also provides
analytic calculations of the relic density in the simplified models and reports
an issue that arose when ATLAS and CMS first began to use preliminary numerical
calculations of the dark matter relic density in these models.Comment: 19 pages, 4 figures; v2: author list and LaTeX problem fixe
Structural characteristics and antiviral activity of multiple peptides derived from MDV glycoproteins B and H
<p>Abstract</p> <p>Background</p> <p>Marek's disease virus (MDV), which is widely considered to be a natural model of virus-induced lymphoma, has the potential to cause tremendous losses in the poultry industry. To investigate the structural basis of MDV membrane fusion and to identify new viral targets for inhibition, we examined the domains of the MDV glycoproteins gH and gB.</p> <p>Results</p> <p>Four peptides derived from the MDV glycoprotein gH (gHH1, gHH2, gHH3, and gHH5) and one peptide derived from gB (gBH1) could efficiently inhibit plaque formation in primary chicken embryo fibroblast cells (CEFs) with 50% inhibitory concentrations (IC<sub>50</sub>) of below 12 μM. These peptides were also significantly able to reduce lesion formation on chorioallantoic membranes (CAMs) of infected chicken embryos at a concentration of 0.5 mM in 60 μl of solution. The HR2 peptide from Newcastle disease virus (NDVHR2) exerted effects on MDV specifically at the stage of virus entry (i.e., in a cell pre-treatment assay and an embryo co-treatment assay), suggesting cross-inhibitory effects of NDV HR2 on MDV infection. None of the peptides exhibited cytotoxic effects at the concentrations tested. Structural characteristics of the five peptides were examined further.</p> <p>Conclusions</p> <p>The five MDV-derived peptides demonstrated potent antiviral activity, not only in plaque formation assays in vitro, but also in lesion formation assays in vivo. The present study examining the antiviral activity of these MDV peptides, which are useful as small-molecule antiviral inhibitors, provides information about the MDV entry mechanism.</p
Cosmic Ray Anomalies from the MSSM?
The recent positron excess in cosmic rays (CR) observed by the PAMELA
satellite may be a signal for dark matter (DM) annihilation. When these
measurements are combined with those from FERMI on the total () flux
and from PAMELA itself on the ratio, these and other results are
difficult to reconcile with traditional models of DM, including the
conventional mSUGRA version of Supersymmetry even if boosts as large as
are allowed. In this paper, we combine the results of a previously
obtained scan over a more general 19-parameter subspace of the MSSM with a
corresponding scan over astrophysical parameters that describe the propagation
of CR. We then ascertain whether or not a good fit to this CR data can be
obtained with relatively small boost factors while simultaneously satisfying
the additional constraints arising from gamma ray data. We find that a specific
subclass of MSSM models where the LSP is mostly pure bino and annihilates
almost exclusively into pairs comes very close to satisfying these
requirements. The lightest in this set of models is found to be
relatively close in mass to the LSP and is in some cases the nLSP. These models
lead to a significant improvement in the overall fit to the data by an amount
dof in comparison to the best fit without Supersymmetry
while employing boosts . The implications of these models for future
experiments are discussed.Comment: 57 pages, 31 figures, references adde
Goldstones in Diphotons
We study the conditions for a new scalar resonance to be observed first in
diphotons at the LHC Run-2. We focus on scenarios where the scalar arises
either from an internal or spacetime symmetry broken spontaneously, for which
the mass is naturally below the cutoff and the low-energy interactions are
fixed by the couplings to the broken currents, UV anomalies, and selection
rules. We discuss the recent excess in diphoton resonance searches observed by
ATLAS and CMS at 750 GeV, and explore its compatibility with other searches at
Run-1 and its interpretation as Goldstone bosons in supersymmetry and composite
Higgs models. We show that two candidates naturally emerge: a Goldstone boson
from an internal symmetry with electromagnetic anomalies, and the scalar
partner of the Goldstone of supersymmetry breaking: the sgoldstino. The dilaton
from conformal symmetry breaking is instead disfavoured by present data, in its
minimal natural realization.Comment: 18 pages + refs, 2 figures. v2: typos corrected, references added,
discussions extended and three new plots. Conclusion unchanged. v3: published
versio
Mechanism of Neutralization of Herpes Simplex Virus by Antibodies Directed at the Fusion Domain of Glycoprotein B
Glycoprotein B (gB), the fusogen of herpes simplex virus (HSV), is a class III fusion protein with a trimeric ectodomain of known structure for the postfusion state. Seen by negative-staining electron microscopy, it presents as a rod with three lobes (base, middle, and crown). gB has four functional regions (FR), defined by the physical location of epitopes recognized by anti-gB neutralizing monoclonal antibodies (MAbs). Located in the base, FR1 contains two internal fusion loops (FLs) and is the site of gB-lipid interaction (the fusion domain). Many of the MAbs to FR1 are neutralizing, block cell-cell fusion, and prevent the association of gB with lipid, suggesting that these MAbs affect FL function. Here we characterize FR1 epitopes by using electron microscopy to visualize purified Fab-gB ectodomain complexes, thus confirming the locations of several epitopes and localizing those of MAbs DL16 and SS63. We also generated MAb-resistant viruses in order to localize the SS55 epitope precisely. Because none of the epitopes of our anti-FR1 MAbs mapped to the FLs, we hyperimmunized rabbits with FL1 or FL2 peptides to generate polyclonal antibodies (PAbs). While the anti-FL1 PAb failed to bind gB, the anti-FL2 PAb had neutralizing activity, implying that the FLs become exposed during virus entry. Unexpectedly, the anti-FL2 PAb (and the anti-FR1 MAbs) bound to liposome-associated gB, suggesting that their epitopes are accessible even when the FLs engage lipid. These studies provide possible mechanisms of action for HSV neutralization and insight into how gB FR1 contributes to viral fusion. IMPORTANCE: For herpesviruses, such as HSV, entry into a target cell involves transfer of the capsid-encased genome of the virus to the target cell after fusion of the lipid envelope of the virus with a lipid membrane of the host. Virus-encoded glycoproteins in the envelope are responsible for fusion. Antibodies to these glycoproteins are important biological tools, providing a way of examining how fusion works. Here we used electron microscopy and other techniques to study a panel of anti-gB antibodies. Some, with virus-neutralizing activity, impair gB-lipid association. We also generated a peptide antibody against one of the gB fusion loops; its properties provide insight into the way the fusion loops function as gB transits from its prefusion form to an active fusogen
Herpes Virus Fusion and Entry: A Story with Many Characters
Herpesviridae comprise a large family of enveloped DNA viruses all of whom employ orthologs of the same three glycoproteins, gB, gH and gL. Additionally, herpesviruses often employ accessory proteins to bind receptors and/or bind the heterodimer gH/gL or even to determine cell tropism. Sorting out how these proteins function has been resolved to a large extent by structural biology coupled with supporting biochemical and biologic evidence. Together with the G protein of vesicular stomatitis virus, gB is a charter member of the Class III fusion proteins. Unlike VSV G, gB only functions when partnered with gH/gL. However, gH/gL does not resemble any known viral fusion protein and there is evidence that its function is to upregulate the fusogenic activity of gB. In the case of herpes simplex virus, gH/gL itself is upregulated into an active state by the conformational change that occurs when gD, the receptor binding protein, binds one of its receptors. In this review we focus primarily on prototypes of the three subfamilies of herpesviruses. We will present our model for how herpes simplex virus (HSV) regulates fusion in series of highly regulated steps. Our model highlights what is known and also provides a framework to address mechanistic questions about fusion by HSV and herpesviruses in general
The pre-fusion structure of Herpes simplex virus glycoprotein B
Cell entry of enveloped viruses requires specialized viral proteins which mediate fusion with the
host membrane by substantial structural rearrangements from a metastable pre- to a stable postfusion
conformation. This metastability renders the Herpes simplex virus (HSV-1) fusion
glycoprotein B (gB) highly unstable such that it readily converts into the post-fusion form, thereby
precluding structural elucidation of the pharmacologically relevant pre-fusion conformation. By
identification of conserved sequence signatures and molecular dynamics simulations, we devised
a mutation that stabilized this form. Functionally locking gB, allowed the structural determination
of its membrane-embedded pre-fusion conformation at sub-nanometer resolution and enabled the
unambiguous fit of all ectodomains. The resulting pseudo-atomic model reveals a striking
conservation of conformational domain rearrangements during fusion between HSV-1 gB and the
Vesicular Stomatitis Virus glycoprotein G (VSV-G) despite their very distant phylogeny. In
combination with our comparative sequence-structure analysis, these findings suggest common
fusogenic domain rearrangements in all class III viral fusion proteins.
Rey, M. Topf, K
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