Atomic Resolution Structure of the Oncolytic Parvovirus LuIII by Electron Microscopy and 3D Image Reconstruction

Pittman, Nikea; Misseldine, Adam; Geilen, Lorena; Halder, Sujata; Smith, J. W. G.; Kurian, Justin; Chipman, Paul R.; Janssen, Mandy E.W.; McKenna, Robert; Baker, Timothy S.; D’Abramo, Anthony; Cotmore, Susan F.; Tattersall, Peter; Agbandje‐McKenna, Mavis

doi:10.3390/v9110321

Cited by 6 publications

(12 citation statements)

References 76 publications

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“…Minor peaks on the DSF curve might be the result of partial unfolding of the capsid or the disassociation of capsid subunits from the whole, either of which would expose hydrophobic residues and result in increased fluorescence. The structure of the M. spretus EVE capsids at a resolution of 3.89 Å confirmed that the capsid structure was very similar to those of other rodent and porcine parvoviruses, with some rearrangements of the variable surface loops, as is customarily seen when comparing these viruses (26,40). M. spretus capsids showed uptake patterns by murine cells that were similar to those of extant mouse parvoviruses, with capsids having a perinuclear localization 1 h after uptake (25) (Fig.…”

Section: Discussionsupporting

confidence: 68%

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Examination and Reconstruction of Three Ancient Endogenous Parvovirus Capsid Protein Gene Remnants Found in Rodent Genomes

Callaway

Subramanian

Urbina

et al. 2019

J Virol

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Parvovirus-derived endogenous viral elements (EVEs) have been found in the genomes of many different animal species, resulting from integration events that may have occurred from more than 50 million years ago to much more recently. Here, we further investigate the properties of autonomous parvovirus EVEs and describe their relationships to contemporary viruses. While we did not find any intact capsid protein open reading frames in the integrated viral sequences, we examined three EVEs that were repaired to form full-length sequences with relatively few changes. These sequences were found in the genomes of Rattus norvegicus (brown rat), Mus spretus (Algerian mouse), and Apodemus sylvaticus (wood mouse). The R. norvegicus sequence was not present in the genomes of the closely related species R. rattus, R. tanezumi, R. exulans, and R. everetti, indicating that it was less than 2 million years old, and the M. spretus and A. sylvaticus sequences were not found in the published genomes of other mouse species, also indicating relatively recent insertions. The M. spretus VP2 sequence assembled into capsids, which had high thermal stability, bound the sialic acid N-acetylneuraminic acid, and entered murine L cells. The 3.89-Å structure of the M. spretus virus-like particles (VLPs), determined using cryo-electron microscopy, showed similarities to rodent and porcine parvovirus capsids. The repaired VP2 sequences from R. norvegicus and A. sylvaticus did not assemble as first prepared, but chimeras combining capsid surface loops from R. norvegicus with canine parvovirus assembled, allowing some of that capsid’s structures and functions to be examined. IMPORTANCE Parvovirus endogenous viral elements (EVEs) that have been incorporated into the genomes of different animals represent remnants of the DNA sequences of ancient viruses that infected the ancestors of those animals millions of years ago, but we know little about their properties or how they differ from currently circulating parvoviruses. By expressing the capsid proteins of different parvovirus EVEs that were found integrated into the genomes of three different rodents, we can examine their structures and functions. A VP2 (major capsid protein) EVE sequence from a mouse genome assembled into capsids that had a similar structure and biophysical properties to extant parvoviruses and also bound sialic acids and entered rodent cells. Chimeras formed from combinations of canine parvovirus and portions of the parvovirus sequences from the brown rat genome allowed us to examine the structures and functions of the surface loops of that EVE capsid.

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Section: Discussionsupporting

confidence: 68%

“…8B). There was a pocket within the dimple of the capsid, near the 2-fold axis, which was similar to the sialic acid binding sites identified for other parvoviruses (26)(27)(28)(29) (Fig. 8C).…”

Section: Figsupporting

confidence: 66%

Examination and Reconstruction of Three Ancient Endogenous Parvovirus Capsid Protein Gene Remnants Found in Rodent Genomes

Callaway

Subramanian

Urbina

et al. 2019

J Virol

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“…For each BuV1, BuV2, and BuV3 genotype, the structures were determined to 2.84, 3.79, and 3.25 Å resolution, respectively, and the VP2 structure ordered from residues 33 to 568, 33 to 567, and 33 to 572, respectively. This range of ~540 ordered residues is consistent with those of crystal and/or cryo-reconstructed structures available for other parvoviruses, including members of the protoparvoviruses [ 16 , 17 , 18 , 19 , 20 , 21 ]. The VP structure conserves the β-barrel (βB–βI) and α-helix A observed for all parvovirus structures.…”

Section: Introductionsupporting

confidence: 83%

“…Default settings were used. For structural comparison, the VP2 structures of these viruses (PDB IDs: CPV, 2CAS; FPV, 1C8E; H-1PV, 4GBT; LuIII, 6B8Q; MVM, 1Z14; PPV, 1K3V) [ 16 , 17 , 18 , 19 , 20 , 21 ] were compared to the BuV1 VP2 structure by secondary structure matching (SSM) in the PDBeFOLD program [ 39 ]. Distance differences at regions of non-overlapping Cα positions, due to deletions and insertions, were measured as described above.…”

Section: Methodsmentioning

confidence: 99%

Atomic Resolution Structures of Human Bufaviruses Determined by Cryo-Electron Microscopy

Ilyas

Mietzsch

Kailasan

et al. 2018

Viruses

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Bufavirus strain 1 (BuV1), a member of the Protoparvovirus genus of the Parvoviridae, was first isolated from fecal samples of children with acute diarrhea in Burkina Faso. Since this initial discovery, BuVs have been isolated in several countries, including Finland, the Netherlands, and Bhutan, in pediatric patients exhibiting similar symptoms. Towards their characterization, the structures of virus-like particles of BuV1, BuV2, and BuV3, the current known genotypes, have been determined by cryo-electron microscopy and image reconstruction to 2.84, 3.79, and 3.25 Å, respectively. The BuVs, 65–73% identical in amino acid sequence, conserve the major viral protein, VP2, structure and general capsid surface features of parvoviruses. These include a core β-barrel (βB-βI), α-helix A, and large surface loops inserted between these elements in VP2. The capsid contains depressions at the icosahedral 2-fold and around the 5-fold axes, and has three separated protrusions surrounding the 3-fold axes. Structure comparison among the BuVs and to available parvovirus structures revealed capsid surface variations and capsid 3-fold protrusions that depart from the single pinwheel arrangement of the animal protoparvoviruses. These structures provide a platform to begin the molecular characterization of these potentially pathogenic viruses.

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“…Those distinct interactions determine the tissue tropism of the AAVs and the gene delivery vectors derived from them (52). Cell infection and the tissue tropisms of the minute virus of mice (MVM) and H1 viruses are in some cases determined by variation in the specific interactions of the capsids with the host sialic acids (53,54). Complex virus-receptor interactions also occur in many other systems.…”

mentioning

confidence: 99%

Complex and Dynamic Interactions between Parvovirus Capsids, Transferrin Receptors, and Antibodies Control Cell Infection and Host Range

Callaway

Welsch

Weichert

et al. 2018

J Virol

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Antibody and receptor binding are key virus/host interactions that control host range and determine the success of infection. Canine and feline parvovirus capsids bind the transferrin receptor type-1 (TfR) to enter host cells, and specific structural interactions appear necessary to prepare the stable capsids for infection. Here we define the details of binding, competition, and occupancy of wild-type and mutant parvovirus capsids with purified receptors and antibodies. TfR/capsid binding interactions depended on the TfR species and varied widely, with no direct relationship between binding affinity and infection. Capsids bound feline, raccoon, and black-backed jackal TfRs at high affinity, but barely bound canine TfRs, which mediated infection efficiently. TfRs from different species also occupied capsids to different levels, with an estimated 1-2 feline TfRs but 12 black-backed jackal TfRs binding each capsid. Multiple alanine substitutions within loop 1 on the capsid surface reduced TfR binding, but substitutions within loop 3 did not, suggesting that loop 1 directly engaged the TfR and loop 3 sterically affected that interaction. Binding and competition between different TfRs and/or antibodies showed complex relationships. Both antibodies 14 and E competed capsids off TfRs, but antibody E could also compete capsids off itself and antibody 14, likely by inducing capsid structural changes. In some cases, the initial TfR or antibody binding event affected subsequent TfR binding, suggesting that capsid structure changes occur after TfR or antibody binding and may impact infection. This shows that precise, host-specific TfR/capsid interactions, beyond simple attachment, are important for successful infection. Host receptor binding is a key step during viral infection, and may control both infection and host range. In addition to binding, some viruses require specific interactions with host receptors in order to infect, and anti-capsid antibodies can potentially disrupt these interactions, leading to neutralization. Here, we examine the interactions between parvovirus capsids, the receptors from different hosts, and anti-capsid antibodies. We show that interactions between parvovirus capsids and host-specific TfRs vary in both affinity and in the numbers of receptors bound, with complex effects on infection. In addition, antibodies binding to two sites on the capsids had different effects on TfR/capsid binding. These experiments confirm that receptor and antibody binding to parvovirus capsids are complex processes and the infection outcome is not determined simply by the affinity of attachment.

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Atomic Resolution Structure of the Oncolytic Parvovirus LuIII by Electron Microscopy and 3D Image Reconstruction

Cited by 6 publications

References 76 publications

Examination and Reconstruction of Three Ancient Endogenous Parvovirus Capsid Protein Gene Remnants Found in Rodent Genomes

Examination and Reconstruction of Three Ancient Endogenous Parvovirus Capsid Protein Gene Remnants Found in Rodent Genomes

Atomic Resolution Structures of Human Bufaviruses Determined by Cryo-Electron Microscopy

Complex and Dynamic Interactions between Parvovirus Capsids, Transferrin Receptors, and Antibodies Control Cell Infection and Host Range

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