scholarly journals CryoEM structure of the EBV ribonucleotide reductase BORF2 and mechanism of APOBEC3B inhibition

2021 ◽  
Author(s):  
Nadine M. Shaban ◽  
Rui Yan ◽  
Ke Shi ◽  
Sofia N. Moraes ◽  
Adam Z. Cheng ◽  
...  
Keyword(s):  
Ribonucleotide Reductase ◽  
Nuclear Dna ◽  
Cytosine Deaminase ◽  
Nucleotide Metabolism ◽  
Structural Elements ◽  
Barr Virus ◽  
Host Interaction ◽  
Binding Surface ◽  
Preferential Binding ◽  
Epstein Barr

AbstractViruses use a plethora of mechanisms to evade immune responses. A new example is neutralization of the nuclear DNA cytosine deaminase APOBEC3B by the Epstein-Barr virus (EBV) ribonucleotide reductase subunit BORF2. Cryo-EM studies of APOBEC3B-BORF2 complexes reveal a large >1000 Å2 binding surface comprised of multiple structural elements from each protein, which effectively blocks the APOBEC3B active site from accessing single-stranded DNA substrates. Evolutionary optimization is suggested by unique insertions in BORF2 absent from other ribonucleotide reductases and preferential binding to APOBEC3B relative to the highly related APOBEC3A and APOBEC3G enzymes. An atomic understanding of this novel pathogen-host interaction may contribute to the development of drugs that block the interaction and liberate the natural antiviral activity of APOBEC3B.One-Sentence SummaryThese studies show how a conserved viral nucleotide metabolism protein is repurposed to inhibit a potent antiviral factor.

scholarly journals Determination of the structural basis for selective binding of Epstein-Barr virus to human complement receptor type 2.

1991 ◽  
Vol 174 (6) ◽  
pp. 1299-1311 ◽  
Author(s):  
D R Martin ◽  
A Yuryev ◽  
K R Kalli ◽  
D T Fearon ◽  
J M Ahearn
Keyword(s):  
Epstein Barr Virus ◽  
Specific Binding ◽  
Glycosylation Site ◽  
Single Amino Acid ◽  
Structural Basis ◽  
Viral Receptor ◽  
Barr Virus ◽  
Preferential Binding ◽  
Epstein Barr ◽  
Species Specific

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that selectively infects and immortalizes human B lymphocytes. One determinant of this narrow tropism is human CR2, the only viral receptor within the superfamily of proteins that contain short consensus repeats (SCRs). Human CR2 serves as a receptor for both C3dg and the gp350/220 glycoprotein of EBV, and binds the monoclonal antibody (mAb) OKB7, which blocks binding of both ligands to the receptor. In contrast, although murine CR2 is capable of binding human C3dg and this interaction can be blocked with the mAb 7G6, it does not bind OKB7 or EBV. We have determined the structural basis for absolute specificity of EBV for human CR2 through characterization of a panel of 24 human-murine chimeric receptors, all of which bind human C3dg. The results indicate that preferential binding of EBV to human CR2 is not due to unique amino acids that are capable of binding the virus, but reflects a distinct receptor conformation that can be achieved in murine CR2 with single amino acid substitutions in two discontinuous regions of the primary structure: replacement of proline at position 15 with the corresponding serine from human CR2, and elimination of a potential N-linked glycosylation site between SCR-1 and SCR-2. Furthermore, species-specific binding of EBV, OKB7, and 7G6 can all be manipulated through substitutions among residues 8-15, suggesting that this octapeptide is part of a structural determinant that is critical for binding of both viral and natural ligands to CR2.

scholarly journals HF-EPR, Raman, UV/VIS Light Spectroscopic, and DFT Studies of the Ribonucleotide Reductase R2 Tyrosyl Radical from Epstein-Barr Virus

PLoS ONE ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. e25022 ◽  
Author(s):  
Ane B. Tomter ◽  
Giorgio Zoppellaro ◽  
Florian Schmitzberger ◽  
Niels H. Andersen ◽  
Anne-Laure Barra ◽  
...  
Keyword(s):  
Ribonucleotide Reductase ◽  
Epstein Barr Virus ◽  
Dft Studies ◽  
Tyrosyl Radical ◽  
Barr Virus ◽  
Ribonucleotide Reductase R2 ◽  
Epstein Barr

scholarly journals The Epstein-Barr Virus (EBV) Deubiquitinating Enzyme BPLF1 Reduces EBV Ribonucleotide Reductase Activity

2009 ◽  
Vol 83 (9) ◽  
pp. 4345-4353 ◽  
Author(s):  
Christopher B. Whitehurst ◽  
Shunbin Ning ◽  
Gretchen L. Bentz ◽  
Florent Dufour ◽  
Edward Gershburg ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ribonucleotide Reductase ◽  
Active Site ◽  
Epstein Barr Virus ◽  
Reductase Activity ◽  
Large Subunit ◽  
Small Subunit ◽  
Deubiquitinating Enzyme ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT A newly discovered virally encoded deubiquitinating enzyme (DUB) is strictly conserved across the Herpesviridae. Epstein-Barr virus (EBV) BPLF1 encodes a tegument protein (3,149 amino acids) that exhibits deubiquitinating (DUB) activity that is lost upon mutation of the active-site cysteine. However, targets for the herpesviral DUBs have remained elusive. To investigate a predicted interaction between EBV BPLF1 and EBV ribonucleotide reductase (RR), a functional clone of the first 246 N-terminal amino acids of BPLF1 (BPLF1 1-246) was constructed. Immunoprecipitation verified an interaction between the small subunit of the viral RR2 and BPLF1 proteins. In addition, the large subunit (RR1) of the RR appeared to be ubiquitinated both in vivo and in vitro; however, ubiquitinated forms of the small subunit, RR2, were not detected. Ubiquitination of RR1 requires the expression of both subunits of the RR complex. Furthermore, coexpression of RR1 and RR2 with BPLF1 1-246 abolishes ubiquitination of RR1. EBV RR1, RR2, and BPLF1 1-246 colocalized to the cytoplasm in HEK 293T cells. Finally, expression of enzymatically active BPLF1 1-246 decreased RR activity, whereas a nonfunctional active-site mutant (BPLF1 C61S) had no effect. These results indicate that the EBV deubiquitinating enzyme interacts with, deubiquitinates, and influences the activity of the EBV RR. This is the first verified protein target of the EBV deubiquitinating enzyme.

scholarly journals Retraction of Mechanistic Basis for Epstein–Barr Virus Ribonucleotide-reductase Small-Subunit Function

2012 ◽  
Vol 7 (10) ◽  
pp. 1764-1764
Author(s):  
Florian Schmitzberger ◽  
Daniel Gurmu ◽  
Sue-Li Dahlroth ◽  
Pär Nordlund
Keyword(s):  
Ribonucleotide Reductase ◽  
Epstein Barr Virus ◽  
Small Subunit ◽  
Barr Virus ◽  
Subunit Function ◽  
Epstein Barr ◽  
Mechanistic Basis

Transcriptional Profiling of Epstein-Barr Virus (EBV) Genes and Host Cellular Genes in Nasal NK/T-Cell Lymphoma and Chronic Active EBV Infection.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4359-4359
Author(s):  
Yu Zhang ◽  
Junko H. Ohyashiki ◽  
Tomoiku Takaku ◽  
Norio Shimizu ◽  
Kazuma Ohyashiki
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lymphoma ◽  
Transcriptional Profiling ◽  
T Cell Lymphoma ◽  
Barr Virus ◽  
Host Interaction ◽  
Cellular Genes ◽  
Nk T Cell ◽  
Epstein Barr

Abstract Nasal NK/T-cell lymphoma is a uniquely aggressive and incurable subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein-Barr virus (EBV). Since necrosis is the common feature of nasal NK/T-cell lymphoma, the biological features of lymphoma cell are poorly understood because of the difficulty in obtaining sufficient viable specimens. The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. Although the molecular biology of EBV and B cell transformation has been extensively studied for years, little is known about the host-virus interaction in EBV-related NK- and T-cell malignancies. This study aimed to investigate the virus-host interaction in two types of EBV-associated NK/T-cell LPD which may clarify the possible association between infection and cancer. We attempted transcriptional profiling of EBV genes using a novel viral DNA microarray, HHV-4 Viruchip®, in addition to host cellular gene expression profiling using human oligonucleotide DNA microarrays, seeking to evaluate the possible role of EBV-host interaction in nasal NK/T-cell lymphoma and CAEBV infection. We used six cell lines with EBV-associated T/NK-cell LPD: SNK-1, SNK-6 and SNT-8 were isolated from nasal NK/T-cell lymphoma, and SNK-10, SNT-13 and SNT-16 were isolated from the peripheral blood of patients with CAEBV infection (Zhang Yu, et al., Br. J. Haematol., 121: 805–814, 2003). We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was preferentially high in cell lines from CAEBV infection. We also analyzed the gene expression patterns of host cellular genes using a pathway-focused human oligonucleotide DNA microarray (NCBI GEO accession number: GPL1919 and GPL 1920). We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD, and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.

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