Journal: J Virol / Year: 2025 Title: Cryo-EM structure of the Seneca Valley virus A-particle and related structural states. Authors: Rosheny Kumaran / Nadishka Jayawardena / Kuan-Lin Chen / Alice-Roza Eruera / James Hodgkinson-Bean / Laura N Burga / Matthias Wolf / Mihnea Bostina / Abstract: Picornavirus cell entry requires a series of capsid protein conformational changes leading to genome uncoating. For enteroviruses, receptor binding triggers the transition from a full (F) capsid to ...Picornavirus cell entry requires a series of capsid protein conformational changes leading to genome uncoating. For enteroviruses, receptor binding triggers the transition from a full (F) capsid to an altered (A) particle before releasing its genome and finally converting it into an empty (E) particle. In contrast, non-enteroviruses, such as Aphthovirus, Cardiovirus, or Seneca Valley virus, release their genomes by dissociating the capsid into pentamers. While the existence of a transient A-particle for non-enteroviruses was previously speculated, it has never been directly observed using structural methods. Seneca Valley virus (SVV) is an oncolytic picornavirus that selectively targets cancer cells by recognizing Tumor endothelial marker 8 (TEM8) as the host receptor. SVV disassembles into pentamers at acidic pH, suggesting that the acidic environment of the endosome could cause capsid disassembly. We used cryo-electron microscopy to investigate SVV under acidic conditions and in complex with TEM8 at physiological pH, identifying multiple uncoating intermediates. These include an altered-particle, an empty-rotated particle (E), and a series of open particles expelling the coiled genome. The A-particle is expanded, displays reduced interactions between capsid proteins, a reorganized genome, and has a poorly resolved VP1 N-terminus, VP2 N-terminus, and VP4. The E particle has rotated pentamers, reduced contacts within the particle, lacks the genome, VP1 and VP2 N-termini, and VP4. Our work provides an understanding of transient SVV structural states and supports the existence of an intermediate SVV A-particle. These findings could help optimize SVV for oncolytic therapy.IMPORTANCESeneca Valley virus (SVV) is a non-enterovirus picornavirus with specific tumor tropism mediated by the receptor Tumor endothelial marker 8, also known as Anthrax toxin receptor 1. Using cryo-electron microscopy, it was possible to identify multiple structural states of SVV. We demonstrate that SVV capsids transition from full particles to altered (A) particles and then to empty-rotated (E) particles, with receptor binding and acidic pH driving these conformational changes, respectively. This study also identifies open particles with expelled genomes. Comparisons between A- and E-particles reveal that peptide segments of VP1, VP2, and VP4 could potentially play a role in genome delivery. Future work can explore the formation of these structural states .
Name: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: CA
Molecular weight
Theoretical: 40.078 Da
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Experimental details
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Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
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Sample preparation
Concentration
0.25 mg/mL
Buffer
pH: 5
Vitrification
Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 310.15 K / Instrument: FEI VITROBOT MARK IV
Details
SVV was incubated at pH 5 for 1 hour. Then, a ratio of 600 receptor particles per capsid was added to the incubated sample. The virus-receptor mixture was incubated at 37 degrees C for 90 minutes. The sample was kept at 37 degrees C until the plunge freezing of cryo-EM grids.
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Electron microscopy
Microscope
TFS KRIOS
Image recording
Film or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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Movie
Controller
Yorodumi
Open data
Basic information
Map data
Sample
Keywords
Function and homology information
Seneca Valley virus USA/SSV-001
Authors
Citation
Structure visualization
Downloads & links
emd_47829.png
http://ftp.pdbj.org/pub/emdb/structures/EMD-47829
Z (Sec.)
Y (Row.)
X (Col.)
Sample components
Processing
Electron microscopy
FIELD EMISSION GUN
