Structural Determinants of Rotavirus Subgroup Specificity Mapped by Cryo-electron Microscopy

Greig, Sarah L.; Berriman, John; O’Brien, Judith A.; Taylor, John A.; Bellamy, A R; Yeager, Mark; Mitra, Alok K.

doi:10.1016/j.jmb.2005.11.049

Cited by 15 publications

(19 citation statements)

References 41 publications

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“…During virion assembly, trimers of VP6 would engage outer surface-exposed VP2 amino acids, encapsulating the core and forming a DLP. The structural location and organization of VP6 trimers around the fivefold axis is slightly different between VP6 SG-I and SG-II rotavirus strains (8). It is feasible that, like VP6, the structure of the core shell varies for VP2 SG-I and SG-II proteins.…”

Section: Discussionmentioning

confidence: 98%

“…The dramatic sequence variation within this important region of the protein might reflect differences in protein-protein or protein-RNA interactions and RNA synthesis for these viruses. In support of this idea, it has been reported that rotavirus strains UK and Wa exhibit different in vitro transcription levels (8). Because UK and Wa show sequence variations in other capsid proteins in addition to VP2, the reason for the disparity in mRNA synthesis is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…The epitope for the VP6 SG-I antibody (255/60) includes residues A172, A305, and R296 to N299 and spans two monomers of a VP6 trimer unit (8,18,32). The epitope for the VP6 SG-II antibody (631/9) includes residues A305, A306, and G315, which are all present on a single chain of the trimerized protein.…”

Section: Discussionmentioning

confidence: 99%

“…These VP6 SG-specific antibodies each bind to a distinct conformational epitope present on the trimeric, but not the monomeric, form of the intermediate capsid protein (8,18,32). Although a small percentage of rotaviruses bear both or neither VP6 epitopes (SG-I/II or non-SG-I/II, respectively), most human strains are VP6 SG-I or SG-II (3,14).…”

mentioning

confidence: 99%

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Molecular Characterization of a Subgroup Specificity Associated with the Rotavirus Inner Capsid Protein VP2

McDonald

Patton

2008

J Virol

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Group A rotaviruses are classified into serotypes, based on the reactivity pattern of neutralizing antibodies to VP4 and VP7, as well as into subgroups (SGs), based on non-neutralizing antibodies directed against VP6. The inner capsid protein (VP2) has also been described as a SG antigen; however, little is known regarding the molecular determinants of VP2 SG specificity. In this study, we characterize VP2 SGs by correlating genetic markers with the immunoreactivity of the SG-specific monoclonal antibody (YO-60). Our results show that VP2 proteins similar in sequence to that of the prototypic human strain Wa are recognized by YO-60, classifying them as VP2 SG-II. In contrast, proteins not bound by YO-60 are similar to those of human strains DS-1 or AU-1 and represent VP2 SG-I. Using a mutagenesis approach, we identified residues that determine recognition by either YO-60 or the group A-specific VP2 monoclonal antibody (6E8). We found that YO-60 binds to a conformationally dependent epitope that includes Wa VP2 residue M328. The epitope for 6E8 is also contingent upon VP2 conformation and resides within a single region of the protein (Wa VP2 residues A440 to T530). Using a high-resolution structure of bovine rotavirus double-layered particles, we predicted these epitopes to be spatially distinct from each other and located on opposite surfaces of VP2. This study reveals the extent of genetic variation among group A rotavirus VP2 proteins and illuminates the molecular basis for a previously described SG specificity associated with the rotavirus inner capsid protein.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular Characterization of a Subgroup Specificity Associated with the Rotavirus Inner Capsid Protein VP2

McDonald

Patton

2008

J Virol

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“…Virus titers were measured by fluorescent focus assay in MA104 cells. Triple-layer particles (TLPs) were purified from cell pellets derived from 10 roller bottles using cesium chloride isopycnic centrifugation as described previously (17).…”

Section: Methodsmentioning

confidence: 99%

Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2

Mansell

Ussher

et al. 2013

J Virol

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Rotavirus is a nonenveloped, double-stranded RNA (dsRNA) virus responsible for acute gastroenteritis in the young of several animal species, including humans (1). The virus infects mature enterocytes present on intestinal villi. Transmission occurs via the fecal-oral route, although recent studies have confirmed extraintestinal spread and viremia in infected patients (2). Within the infected cell, six structural proteins (VP1 to VP4, VP6, and VP7) assemble into three concentric capsid layers that encase the segmented dsRNA genome (3, 4). Five nonstructural proteins (NSP1 to NSP5) are also synthesized in infected cells, and these play various roles in the replication of the viral genome, translation of viral mRNA, and virion morphogenesis (5).NSP4 is a transmembrane glycoprotein with an essential role in the assembly of intermediate double-layered particles and their maturation to infectious virions within the infected cell. NSP4 is also actively secreted from virus-infected polarized epithelial cells in its full-length form after specific posttranslational modification (6). The range of cellular and physiological effects attributed to exogenous NSP4 includes the ability to act as a virus-encoded enterotoxin capable of inducing dose-and age-dependent diarrhea in mice and rats (7), potentiation of Cl Ϫ and water secretion from noninfected epithelia (8), disruption of transepithelial resistance (9), and direct inhibition of the Na ϩ -D-glucose symporter transporter (10). Recombinant forms of NSP4 representing either the full-length protein or regions of the cytoplasmic domain have been demonstrated to cause the phospholipase C (PLC)-dependent elevation of intracellular Ca 2ϩ ions (11) and secretion of 5-hydroxytryptamine (5-HT) from enteroendocrine cells (12).Collectively, these studies indicate that NSP4 secreted from rotavirus-infected cells can interact with a range of cell types in vivo, initiate signaling pathways that affect the local physiology of the small intestine, and contribute to the clinical symptoms of rotavirus infection. Nevertheless, there remains a paucity of experimental data indicating how these apparently pleiotropic effects are regulated. For example, the nature and identity of plasma membrane receptors that activate intracellular signaling pathways in response to exogenous NSP4 are not well defined. Seo et al.reported that recombinant NSP4 can bind to the metal ion-dependent adhesion site (MIDAS) motif present on integrins ␣1␤1 and ␣2␤1 and activate intracellular signaling pathways that regulate cell spreading (13). Mutations in NSP4 that reduce integrin binding also correlated with an inability to cause diarrhea in mice. However, given the wide range of effects reported for NSP4, it is feasible that non-integrin receptors exist.The majority of studies into the cellular effects of NSP4 have focused on primary enterocytes and cell lines of intestinal epithelial origin. We observed recently that NSP4, purified from the medium of rotavirus-infected cells, bound to a wide range of cells of disti...

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Molecular characterization of VP6‐encoding gene of group A human rotavirus samples from central west region of Brazil

Tavares¹,

Brito²,

Fiaccadori³

et al. 2008

Journal of Medical Virology

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Group A rotaviruses are the main cause of acute gastroenteritis in children worldwide. The intermediate capsid protein VP6 encoded by segment 6 of the dsRNA genome is the major structural component of the virus and it is highly antigenic and immunogenic. VP6 is responsible for group and subgroup (SG) specificities, allowing classification of group A rotavirus into SG I, SG II, SG I + II, and SG non-I-non-II. VP6-encoding gene of 154 group A human rotavirus samples of different G and P genotypes recovered from children in three cities of Central West region of Brazil was amplified by reverse transcription-polymerase chain reaction followed by sequencing and phylogenetic analysis. Two distinct genetic groups could be recognized: VP6 genogroups I and II. Sequences analysis also revealed that all samples identified as VP6 genogroup I were associated with NSP4 genotype A, whereas samples identified as VP6 genogroup II were associated with NSP4 genotype B. This is the first study in Central West region regarding genetic variability of the VP6 gene. Further molecular surveillance of rotavirus strains is needed to understand better the occurrence of VP6 gene diversity in Brazil and the significance of VP6 for the control and prevention of rotavirus gastroenteritis.

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Structural Determinants of Rotavirus Subgroup Specificity Mapped by Cryo-electron Microscopy

Cited by 15 publications

References 41 publications

Molecular Characterization of a Subgroup Specificity Associated with the Rotavirus Inner Capsid Protein VP2

Molecular Characterization of a Subgroup Specificity Associated with the Rotavirus Inner Capsid Protein VP2

Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2

Molecular characterization of VP6‐encoding gene of group A human rotavirus samples from central west region of Brazil

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