scholarly journals Seneca Valley virus attachment and uncoating mediated by its receptor anthrax toxin receptor 1

2018 ◽  
Vol 115 (51) ◽  
pp. 13087-13092 ◽  
Author(s):  
Lin Cao ◽  
Ran Zhang ◽  
Tingting Liu ◽  
Zixian Sun ◽  
Mingxu Hu ◽  
...  
Keyword(s):  
Metal Ion ◽  
Structural Changes ◽  
Attachment Site ◽  
Cell Entry ◽  
Anthrax Toxin ◽  
Virus Propagation ◽  
Virus Attachment ◽  
Toxin Receptor ◽  
Seneca Valley Virus ◽  
Acidic Conditions

Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. SVV mediates cell entry by attachment to the receptor anthrax toxin receptor 1 (ANTXR1). Here we determine atomic structures of mature SVV particles alone and in complex with ANTXR1 in both neutral and acidic conditions, as well as empty “spent” particles in complex with ANTXR1 in acidic conditions by cryoelectron microscopy. SVV engages ANTXR1 mainly by the VP2 DF and VP1 CD loops, leading to structural changes in the VP1 GH loop and VP3 GH loop, which attenuate interprotomer interactions and destabilize the capsid assembly. Despite lying on the edge of the attachment site, VP2 D146 interacts with the metal ion in ANTXR1 and is required for cell entry. Though the individual substitution of most interacting residues abolishes receptor binding and virus propagation, a serine-to-alanine mutation at VP2 S177 significantly increases SVV proliferation. Acidification of the SVV–ANTXR1 complex results in a major reconfiguration of the pentameric capsid assemblies, which rotate ∼20° around the icosahedral fivefold axes to form a previously uncharacterized spent particle resembling a potential uncoating intermediate with remarkable perforations at both two- and threefold axes. These structures provide high-resolution snapshots of SVV entry, highlighting opportunities for anticancer therapeutic optimization.

scholarly journals Structural basis for anthrax toxin receptor 1 recognition by Seneca Valley Virus

2018 ◽  
Vol 115 (46) ◽  
pp. E10934-E10940 ◽  
Author(s):  
Nadishka Jayawardena ◽  
Laura N. Burga ◽  
Richard A. Easingwood ◽  
Yoshimasa Takizawa ◽  
Matthias Wolf ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protective Antigen ◽  
Therapeutic Option ◽  
Oncolytic Viruses ◽  
Anthrax Toxin ◽  
Bacterial Toxin ◽  
Structural Basis ◽  
Electron Microscopy Analysis ◽  
Toxin Receptor ◽  
Seneca Valley Virus

Recently, the use of oncolytic viruses in cancer therapy has become a realistic therapeutic option. Seneca Valley Virus (SVV) is a newly discovered picornavirus, which has earned a significant reputation as a potent oncolytic agent. Anthrax toxin receptor 1 (ANTXR1), one of the cellular receptors for the protective antigen secreted by Bacillus anthracis, has been identified as the high-affinity cellular receptor for SVV. Here, we report the structure of the SVV-ANTXR1 complex determined by single-particle cryo-electron microscopy analysis at near-atomic resolution. This is an example of a shared receptor structure between a mammalian virus and a bacterial toxin. Our structure shows that ANTXR1 decorates the outer surface of the SVV capsid and interacts with the surface-exposed BC loop and loop II of VP1, “the puff” of VP2 and “the knob” of VP3. Comparison of the receptor-bound capsid structure with the native capsid structure reveals that receptor binding induces minor conformational changes in SVV capsid structure, suggesting the role of ANTXR1 as an attachment receptor. Furthermore, our results demonstrate that the capsid footprint on the receptor is not conserved in anthrax toxin receptor 2 (ANTXR2), thereby providing a molecular mechanism for explaining the exquisite selectivity of SVV for ANTXR1.

scholarly journals A canstatin-derived peptide provides insight into the role of Capillary Morphogenesis Gene 2 in angiogenic regulation and matrix uptake

2019 ◽  
Author(s):  
Jordan G. Finnell ◽  
Tsz-Ming Tsang ◽  
Lorna Cryan ◽  
Samuel Garrard ◽  
Sai-Lun Lee ◽  
...  
Keyword(s):  
Metal Ion ◽  
Protective Antigen ◽  
Anthrax Toxin ◽  
Peptide Array ◽  
Peptide Fragments ◽  
Capillary Morphogenesis ◽  
Type Iv ◽  
Toxin Receptor ◽  
Affinity Peptide ◽  
Von Willebrand

AbstractCapillary Morphogenesis Gene 2 protein (CMG2) is a transmembrane, integrin-like receptor and the primary receptor for the anthrax toxin. In addition to its role as an anthrax toxin receptor, CMG2 has been repeatedly shown to play a role in angiogenic processes. However, the molecular mechanism mediating observed CMG2-related angiogenic effects has not been fully elucidated. Previous studies have found that CMG2 binds type IV collagen (Col-IV), a key component of the vascular basement membrane, as well as other ECM proteins. Currently, no link has been made between these CMG2-ECM interactions and angiogenesis; however, ECM fragments are known to play a role in regulating angiogenesis. Here, we further characterize the CMG2-Col-IV interaction and explore the effect of this interaction on angiogenesis. Using a peptide array, we observed that CMG2 preferentially binds peptide fragments of the NC1 (non-collagenous domain 1) domains of Col-IV. These domains are also known as the fragments arresten (from the α1 chain) and canstatin (from the α2 chain) and have documented antiangiogenic properties. A second peptide array was probed to map a putative binding epitope. A top hit from the initial array, a canstatin-derived peptide, binds to the CMG2 ligand-binding von Willebrand factor A (vWA) domain with sub-micromolar affinity (peptide S16, Kd = 400 ± 200 nM). This peptide competes with anthrax protective antigen (PA) for CMG2 binding, and does not bind CMG2 in the presence of EDTA. Together these data suggest that, like PA, S16 interacts with CMG2 at the metal-ion dependent adhesion site (MIDAS) of its vWA domain. We demonstrate that CMG2 specifically mediates endocytic uptake of S16, since CMG2-/- endothelial cells show markedly reduced S16 uptake, without reducing total endocytosis. Furthermore, we show that S16 reduces endothelial migration but not cell proliferation. Taken together, our data demonstrate that a Col IV-derived anti-angiogenic peptide acts via CMG2, suggesting a possible link between CMG2-Col IV interactions and angiogenesis.

scholarly journals Anthrax toxin receptor 1 is the cellular receptor for Seneca Valley virus

2017 ◽  
Vol 127 (8) ◽  
pp. 2957-2967 ◽  
Author(s):  
Linde A. Miles ◽  
Laura N. Burga ◽  
Eric E. Gardner ◽  
Mihnea Bostina ◽  
John T. Poirier ◽  
...  
Keyword(s):  
Anthrax Toxin ◽  
Cellular Receptor ◽  
Toxin Receptor ◽  
Seneca Valley Virus

scholarly journals N-Linked Glycosylation on Anthrax Toxin Receptor 1 Is Essential for Seneca Valley Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 769
Author(s):  
Nadishka Jayawardena ◽  
Linde A. Miles ◽  
Laura N. Burga ◽  
Charles Rudin ◽  
Matthias Wolf ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Cancer Therapeutics ◽  
Anthrax Toxin ◽  
Mass Spectrometry Analysis ◽  
Type I ◽  
Post Translational Modification ◽  
Spectrometry Analysis ◽  
Toxin Receptor ◽  
Seneca Valley Virus ◽  
Complex Glycans

Seneca Valley virus (SVV) is a picornavirus with potency in selectively infecting and lysing cancerous cells. The cellular receptor for SVV mediating the selective tropism for tumors is anthrax toxin receptor 1 (ANTXR1), a type I transmembrane protein expressed in tumors. Similar to other mammalian receptors, ANTXR1 has been shown to harbor N-linked glycosylation sites in its extracellular vWA domain. However, the exact role of ANTXR1 glycosylation on SVV attachment and cellular entry was unknown. Here we show that N-linked glycosylation in the ANTXR1 vWA domain is necessary for SVV attachment and entry. In our study, tandem mass spectrometry analysis of recombinant ANTXR1-Fc revealed the presence of complex glycans at N166, N184 in the vWA domain, and N81 in the Fc domain. Symmetry-expanded cryo-EM reconstruction of SVV-ANTXR1-Fc further validated the presence of N166 and N184 in the vWA domain. Cell blocking, co-immunoprecipitation, and plaque formation assays confirmed that deglycosylation of ANTXR1 prevents SVV attachment and subsequent entry. Overall, our results identified N-glycosylation in ANTXR1 as a necessary post-translational modification for establishing stable interactions with SVV. We anticipate our findings will aid in selecting patients for future cancer therapeutics, where screening for both ANTXR1 and its glycosylation could lead to an improved outcome from SVV therapy.

scholarly journals Electrochemical Conversion: Beyond the First Cycle

2014 ◽  
Vol 70 (a1) ◽  
pp. C361-C361
Author(s):  
Tiffany Kinnibrugh ◽  
Kamila Wiaderek ◽  
Olaf Borkiewicz ◽  
Nathalie Pereira ◽  
Glenn Amatucci ◽  
...  
Keyword(s):  
Metal Ion ◽  
Pair Distribution Function ◽  
Structural Changes ◽  
Electrode Materials ◽  
Commercial Application ◽  
Structural Studies ◽  
Electrochemical Conversion ◽  
Pdf Analysis ◽  
Intercalation Materials ◽  
Repeated Cycling

Conversion based electrode materials offer increased energy storage compared to conventional intercalation materials due to the multiple electrons that reacts per metal ion. However, loss in capacities upon repeated cycling has limited the development of this technology for commercial application. Most structural studies focus on the first discharge-charge cycle [1,2,3]. To understand the loss in capacities with repeated cycling, studies must be extended beyond the first cycle. In conversion reactions, large structural transformations occur such that the electrode is reduced to the nanoscale. Pair distribution function (PDF) analysis is well suited to characterize the structural changes occurring in such nanomaterials. Conversion based iron fluorides (FeF3, FeF2, and FeOF) have been a focus of both structural and mechanistic studies [1,2,3]. An in-depth PDF analysis of what happens beyond the first cycle will be presented for these.

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