- Open Access
Interaction of mumps virus V protein variants with STAT1-STAT2 heterodimer: experimental and theoretical studies
© Rosas-Murrieta et al; licensee BioMed Central Ltd. 2010
- Received: 11 June 2010
- Accepted: 11 October 2010
- Published: 11 October 2010
Mumps virus V protein has the ability to inhibit the interferon-mediated antiviral response by inducing degradation of STAT proteins. Two virus variants purified from Urabe AM9 mumps virus vaccine differ in their replication and transcription efficiency in cells primed with interferon. Virus susceptibility to IFN was associated with insertion of a non-coded glycine at position 156 in the V protein (VGly) of one virus variant, whereas resistance to IFN was associated with preservation of wild-type phenotype in the V protein (VWT) of the other variant.
VWT and VGly variants of mumps virus were cloned and sequenced from Urabe AM9 vaccine strain. VGly differs from VWT protein because it possesses an amino acid change Gln103Pro (Pro103) and the Gly156 insertion. The effect of V protein variants on components of the interferon-stimulated gene factor 3 (ISGF3), STAT1 and STAT2 proteins were experimentally tested in cervical carcinoma cell lines. Expression of VWT protein decreased STAT1 phosphorylation, whereas VGly had no inhibitory effect on either STAT1 or STAT2 phosphorylation. For theoretical analysis of the interaction between V proteins and STAT proteins, 3D structural models of VWT and VGly were predicted by comparing with simian virus 5 (SV5) V protein structure in complex with STAT1-STAT2 heterodimer. In silico analysis showed that VWT-STAT1-STAT2 complex occurs through the V protein Trp-motif (W174, W178, W189) and Glu95 residue close to the Arg409 and Lys415 of the nuclear localization signal (NLS) of STAT2, leaving exposed STAT1 Lys residues (K85, K87, K296, K413, K525, K679, K685), which are susceptible to proteasome degradation. In contrast, the interaction between VGly and STAT1-STAT2 heterodimer occurs in a region far from the NLS of STAT2 without blocking of Lys residues in both STAT1 and STAT2.
Our results suggest that VWT protein of Urabe AM9 strain of mumps virus may be more efficient than VGly to inactivate both the IFN signaling pathway and antiviral response due to differences in their finest molecular interaction with STAT proteins.
- Nuclear Localization Signal
- Versus Protein
- Mumps Virus
- Cervical Carcinoma Cell Line
- Mumps Vaccine
Interferon induces the major defense against viral infections. It begins with attachment of IFN-α or -β to heterodimeric receptors composed of IFNAR1 and IFNAR2 subunits whose intracellular domains are associated with Tyk2 and Jak1 tyrosine kinases, respectively . Activation of the signal transduction occurs when Tyk2 phosphorylates Tyr466 residue on IFNAR1, creating a docking site for STAT2 that is phosphorylated on Tyr690. Phosphorylated STAT2 protein then associates with STAT2, inducing its phosphorylation on Tyr701 by JAK1 [2, 3]. STAT1 and STAT2 form a heterodimer that creates a nuclear localization signal (NLS). STAT1-STAT2 heterodimers result from intermolecular interactions between Src homology 2 (SH2) domains and phosphorylated Tyr residues at each protein . In addition, IFNAR2 subunit is acetylated at Lys399 and promotes the acetylation of IRF9, which is essential to DNA binding [5, 6]. Association of STAT1-STAT2 heterodimer with IRF9 constitutes the IFN-stimulated gene factor 3 (ISGF3) transcription factor, which binds to IFN-stimulated response elements (ISRE) at IFN-stimulated genes (ISG). The final step of this signaling pathway is the induction of gene transcription whose expression establishes the antiviral state [2, 7]. Several viruses have evolved strategies to circumvent the antiviral state stimulated by IFN through the expression of proteins that antagonize some components of the IFN signaling pathway such as the V protein of paramyxoviruses . Mumps virus P gene codes for three polypeptides: V, I and P. Their mRNAs are translated by use of overlapping reading frames (ORFs) via cotranscriptional insertion of nontemplated guanidine nucleotides (mRNA edition) [9, 10]. Mumps virus V protein is a nonstructural protein that counteracts the IFN-induced antiviral response .
Paramyxovirus V proteins possess an identical N-terminal sequence with P and I proteins but have a unique C-terminal that contains two functional motifs . The first is the cysteine-rich (Cys-rich) motif (CX3CX11CXCX2CX3CX2C) where × refers to any amino acid residue that establishes a stoichiometric relationship (1:2) with Zn2+. Cys-rich motif is highly conserved among rubulaviruses such as simian virus 5 (SV5), simian virus 41 (SV41), human parainfluenza virus type 2 (hPIV2), and mumps virus. Cys-rich motif promotes the formation of an oligomer that acts as a nucleation site known as V-dependent degradation complex (VDC) where both polyubiquitylation and degradation of STAT1 occur [12, 13]. The V proteins of mumps virus and SV5 induce the degradation of STAT1 protein through the VDC assembly that includes ubiquitin ligase E3, Roc1, Cul4A, and DDB1 proteins that facilitate polyubiquitylation of STAT1 [13, 14]. The second C-terminal motif is also involved in STAT1 degradation and is a Trp-motif (W-(X)3-W-(X)9-W) that includes W174, W178 and W188 residues located upstream of the Cys-rich motif [15, 16]. The C-terminal of V protein is essential for successful viral infection by inhibition of IFN signaling and blocking of the antiviral response . In this study we analyzed two variants of mumps virus V protein (VWT and VGly) derived from Urabe AM9 vaccine strain. Previous studies have shown that Urabe AM9 vaccine is constituted by several quasispecies that differ in distinct sites all along their genomes. We purified two virus variants based on the sequence of their HN gene and were named HN-A1081 and HN-G1081, which codes for HN-K335 and HN-E335 proteins, respectively. Several studies have related HN-A1081 with neurovirulence because this virus variant was frequently isolated from patients with postvaccine aseptic meningitis . We demonstrated that HN-A1081 variant preferentially infects nerve cells, whereas HN-G1081 variant has limited replication in nerve cells. Selective infection of nerve cells was associated with differences in the virus binding affinity towards cell receptors . However, further experiments showed that differences in sensitivity to IFN determined the replication rate of Urabe AM9 mumps virus variants in nerve cells. Indeed, HN-A1081 virus variant evaded the IFN-induced antiviral response and replicated in cells primed with IFN, whereas HN-G1081 variant reduced both replication and transcription in IFN-primed cells . Sensitivity to IFN was associated with insertion of a non-coded glycine at position 156 in the V protein (VGly) of HN-G1081 virus variant, whereas resistance to IFN was associated with preservation of wild-type phenotype in the V protein (VWT) of HN-A1081 Virus variant. In the present study we experimentally tested the interaction of VWT and VGly proteins of Urabe AM9 mumps virus variants with proteins of the IFN signaling pathway, finding differences in their capacity to bind STAT proteins. In addition, in silico three- dimensional structure models of VWT and VGly proteins supported their difference to form complexes with STAT1 and STAT2 in vitro. The relevance of these theoretical findings in the function of V protein and virulence of mumps virus variants are discussed.
In order to determine the effect of protein V of the majority populations that comprise the Urabe AM9 vaccine strain on the IFN pathway, we obtained the coding region for V proteins from HN-A1081 and HN-G1081 virus variants, which were cloned in the pcDNA4/HisMax TOPO vector (pcDNA4/HisMaxVA and pcDNA4/HisMaxVG) to add a His-tag at the amino end. Next, the full sequence of V ORF was determined (675 bp), and in silico translation was carried out by comparative analysis. Amino acid differences between V proteins were determined by comparison with the V protein from Urabe AM9 (SmithKline Beecham) (Protein: AAK60067.1). The VA protein containing only 224 residues similar to the wild-type V protein type was named VWT (28.17 kDa). The VG protein contained two changes on residue 103, Q→P, and the addition of a glycine residue at position 156, which generated a V protein with 225 amino acids and was designated VGly (28.13 kDa). Comparing both V proteins, there were no significant changes in the theoretical physicochemical parameters.
None of the variants changed the level of active STAT2 protein as determined with other strains of mumps virus. To test whether the result in Figure 1B was due only to reduction of active STAT1 protein or by degradation of STAT1 unphosphorylated protein, we studied the level of inactive STAT1. Figure 1C shows that in cells expressing VWT and VGly proteins there are no changes in the level of STAT1 protein. This suggests that VWT protein of Urabe AM9 affects the STAT1 phosphorylated protein in blocking type I IFN system. In other strains of mumps virus and SV5, reduction of the STAT1 protein was always determined in the heterodimer with STAT2 phosphorylated protein with the subsequent blockade of the IFN system . Figure 1B, C suggests a differential effect of the V proteins of Urabe AM9 strain vaccine on antiviral cellular response, which may be due to different interactions of VWT and VGly proteins with STAT1-STAT2 heterodimer.
The lack of antiviral for specific control of mumps virus infection requires the study of the molecular mechanism of replication and viral expression to propose sites related to the blocking of viral infection. The Urabe AM9 mumps vaccine is associated with virulence and is composed of at least two viral variants [18, 28, 29]. HN-A1081 variant selectively and preferentially infects nerve cells, whereas HN-G1081 has limited replication in these cells. It is interesting to explore the differences of the potential determinants of a successful viral infection in the nervous system [18, 19]. Considering that V protein of the Paramyxoviridae family is a factor that facilitates viral replication by blocking certain steps in the IFN pathway, there may be a difference between V proteins from Urabe AM9. We currently know that the V protein from wild-type mumps virus, Torri and Enders strains, is associated with STAT1-STAT2 to prevent antiviral cellular response [11, 13, 30, 31].
In this study we analyzed both in vitro and in silico two variants of V protein Urabe AM9: VWT (related to aseptic meningitis) and VGly. Amino acid sequence analysis showed that VGly is different from VWT at Pro103 and Gly156. Such changes altered the theoretical 3D structure and possibly its anti-IFN function. The analysis of the effect of the V protein on STATs proteins showed the efficiency of VWT protein to promote the reduction of STAT1 active protein, whereas VGly protein did not affect its level. This fact has been demonstrated in others strains [13, 21, 26, 31]. Such data suggest that the structural changes on VGly induced by rearrangement of loops and residues of the Cys-rich and Trp-motifs following the addition of Gly156 may be responsible for the loss of efficiency in inducing degradation of the STAT1 protein. This could explain the differences reported in the replication and transcription of genes in response to interferon during infection with the variant HN-G1081 (VGly) of Urabe AM9 where the induction of genes in response to interferon is higher than in the presence of an infection with the variant HN-A1081 (VWT) . However, we cannot conclude if the changes induced by the addition of Gly156 and the low efficiency in the degradation of STAT1 protein for the variant VGly are conferred by inefficient interaction with the proteins involved in the ubiquitylation and degradation by the proteasome system (E2, DDB1, Cullin, Roc1) . These must be confirmed experimentally. To outline a likely explanation, it was predicted the theoretical 3D structure of VWT and VGly by homology modeling. Although the 2B5Lc template lack three loops not resolved by X-ray diffraction, the program modeled two mobile loops but we cannot provide a conclusion of the modeled structure without the template for comparison. The changes mentioned in the VGly modified the theoretical 3D structure, particularly in the loops that limit the Cys-rich motif. The residues of these motifs in VGly move away from Gly155 (present in both proteins), altering the 3D distribution. It is possible that residues in Cys and Trp motifs of VWT are those related to the activity anti-IFN of the V protein of Urabe AM9 mumps vaccine.
At the experimental level, the intermolecular interaction of mumps virus V protein and V-SV5 with the cellular protein of type I IFN by the VDC complex has been demonstrated: STAT1-STAT2 (both phosphorylated), DDB1, Cullin 4A and Roc1 . Interestingly, the interaction of VWT occurs through STAT2, an area near NLS residues  that would prevent their importation to the nucleus by steric hindrance. The theoretical interaction with
STAT2 could maintain the heterodimer in the cytoplasm where the ubiquitin/proteasome labels the lysine-susceptible residues exposed in STAT1. In vivo, it has been shown that the promotion of degradation of STAT1 by the V protein of MuV and V-SV5 is dependent on
STAT2 in the VDC complex [13, 14, 21, 26, 33, 34]. In any case it would block signal transduction of type I IFN to the nucleus, avoiding the antiviral cellular state favorable to viral replication of HN-A1081 variant of Urabe AM9. Instead, in silico analysis of the theoretical interaction between VGly and STAT1-STAT2 showed that the contact occurs through STAT2 as in VWT but in a region far from residues of the NLS on STAT1/STAT2. This would suggest that the heterodimer may advance to the nucleus for exercising its transcriptional activity, although the majority of lysine residues able to bind to ubiquitin are exposed. Although the comparison of the interaction parameters showed that the complex VGly with the STATs proteins may be more stable in terms of overall energy interaction, the attractive and repulsive van der Waals forces were higher in the complex between VWT and
STAT1-STAT2 proteins. The data obtained would explain the reduced capacity of VGly to block the IFN transduction signal, generating a cellular environment unfavorable for viral infection .
The in silico analysis suggests that, in vivo, VWT may be more efficient than VGly to associate with the STATs proteins and probably for blocking the IFN transduction signal as a mechanism to avoid the antiviral defense.
The cervical carcinoma cell lines HeLa and C33A were used for transfections assays and were maintained in Dulbecco's minimum essential medium (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (Gibco-BRL, Grand Island, NY), 100 U/mL penicillin, 100 μg/mL streptomycin and 1% nonessential amino acids (Sigma, St. Louis, MO, USA). Cells were incubated at 37°C in 5% CO2.
Subcloning of VA and VG ORF
The cloning of VA and VG ORF were performed by PCR from pCR-TOPO-VA and pCRTOPO-VG building in a previous work  with the oligonucleotides MuV-1 D 5'-GACCAATTTATAAAACAAGATGAGACTGGT-3' and MuV2 5'-TCCATCCCTCTAAGGAGGTCC-3' (IDT, Coralville, IA). PCR fragment was subcloned in the pCDNA4/HisMax TOPO vector (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions. This vector added a His-tag at the N-terminal of V proteins. Recombinant DNA was transformed in E. coli TOP 10 One Shot (Invitrogen, Carlsbad, CA, USA). Positive clones were sequenced by Big Dye ABI chemistry.
Transient transfection assay and IFN treatment
A monolayer of adenocarcinome cervix cells grown to 80% confluence on flasks of 25 cm2 was transfected with 6 μg of vector DNA (pCDNA4/His/Max-VA and VG) and TurboFect transfection reagent (Fermentas, Glen Burnie, MD, USA) according to the manufacturer's instructions. After cultivation for 24 h, the cells were stimulated with the proteasome inhibitor MG132 (40 μM) (Sigma, St. Louis, MO, USA). At 42 h after transfection, the cells were treated with 4000 IU/mL of IFN-α2b (Urifrón) (Probiomed, Mexico) for 6 h.
Western Blot Analysis
After the stimulation with IFN-α2b and MG132, the cells were lysed with ProteoJET Mammalian Cell Lysis Reagent (Fermentas, Glen Burnie, MD, USA), and the cell lysates were lyophilized and solubilized by boiling for 10 min with sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) sample buffer (62.5 mM Tris-HCl pH 6.8, 5% 2-mercaptoethanol, 2% SDS, 0.005% bromophenol blue, 10% glycerol). The proteins were transferred to a PVDF membrane (0.45 μm) (Santa Cruz Biotechnology, Santa Cruz, CA, USA). The membrane was treated with primary antibody (p-Tyr701 Stat1: sc-7988, p-Tyr690 Stat2: sc-21689, ISGF-3 p48: sc-10793, Actin: sc-8432, His-probe: sc-8036 (Santa Cruz Biotechnology) for 1 h and then incubated with the secondary antibody (bovine antirabbit IgG-HRP: sc-2370) (Santa Cruz Biotechnology) for 1 h. After extensive washing, the immunoreactive bands were detected with Immobilon Chemiluminiscent substrate (Millipore Corporation, Bedford, MA, USA). For detection of the ISGF3 complex, proteins were separated by electrophoresis through 7.5% polyacrylamide gels, transferred to PDVF membranes, and detected with the previously mentioned antibodies.
Generation and analysis of 3D protein models
The prediction for homology of the 3D protein structure was performed with the Swiss-Model program  using as template the structure of V protein simian virus 5 (V-SV5) at 2.85 Å by X-ray diffraction . Neighboring protein structures of mumps virus V proteins were obtained with VAST search . Theoretical 3D structure of VWT and VGly was visualized with Web Lab Viewer program. The final theoretical 3D structures were analyzed with PROCHEK of Swiss-Model [37, 38] and with PROSA . The theoretical 3D model of STAT2 was obtained for homology on Geno3D  from the PDB: 1BF5 (Tyrosine phosphorylated STAT-1/DNA complex)  and PDB: 1YVL. Electrostatic potential was obtained with the Poisson-Boltzmann method in Deep View from Swiss PDB Viewer. The differences between VWT and VGly were analyzed in the SuperPose program . Polyubiquitylation sites in STATs proteins were predicted with UniPred , considering as probable those Lys residues with a minimum score of 0.7 to 1.
Theoretical heterodimer STAT1-STAT2 model was obtained by a docking analysis with Hex server . The putative interaction models between VWT and VGly with STAT1-STAT2 proteins were generated with PatchDock server (Molecular Docking Algorithm Based on Shape Complementary Principles)  and 1000 theoretical models were refined on FireDock (Fast Interaction Refinement in Molecular Docking) .
This work was supported by SEP-PROMEP Grant 103.5/07/2594 and CONACyT-Salud 2003-C01-085.
- Goodbourn S, Didcock L, Randall RE: Interferons: cell signaling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 2000,81(10):2341-2364.PubMedView ArticleGoogle Scholar
- Randall RE, Goodbourn S: Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 2008,89(1):1-47. 10.1099/vir.0.83391-0PubMedView ArticleGoogle Scholar
- de Weerd NA, Samarajiwa SA, Hertzog PJ: Type I interferon receptors: biochemistry and biological functions. J Biol Cel 2007,282(28):20053-20057.Google Scholar
- Samuel CE: Antiviral actions of interferons. Clin Microbiol Rev 2001,14(4):778-809. 10.1128/CMR.14.4.778-809.2001PubMedPubMed CentralView ArticleGoogle Scholar
- Banninger G, Reich NC: STAT2 nuclear trafficking. J Biol Chem 2004,279(38):39199-39206. 10.1074/jbc.M400815200PubMedView ArticleGoogle Scholar
- Tang X, Gao JS, Guan YJ, McLane KE, Yuan ZL, Ramratnam B, Chin YE: Acetylation-dependent signal transduction for type I interferon receptor. Cell 2007,131(1):93-105. 10.1016/j.cell.2007.07.034PubMedView ArticleGoogle Scholar
- Murray PJ: The JAK-STAT signaling pathway: input and output integration. J Immunol 2007,178(5):2623-2629.PubMedView ArticleGoogle Scholar
- Horvath CM: Weapons of STAT destruction. Eur J Biochem 2004,271(23-24):4621-4628. 10.1111/j.1432-1033.2004.04425.xPubMedView ArticleGoogle Scholar
- Lamb RA, Kolakofsky D: Paramyxoviridae: the viruses and their replication. In Fields Virology. 4th edition. Edited by: Fields BN, Knipe DM, Howley PM, Griffin DE. Philadelphia: Lippincott-Raven Publishers; 2001:1305-1340.Google Scholar
- Paterson RG, Lamb RA: RNA editing by G-nucleotide insertion in mumps virus P-gene mRNA transcripts. J Virol 1990,64(9):4137-4145.PubMedPubMed CentralGoogle Scholar
- Gotoh B, Komatsu T, Takeuchi K, Yokoo J: Paramyxovirus accessory proteins as interferon antagonists. Microbiol Immunol 2001,45(12):787-800.PubMedView ArticleGoogle Scholar
- Kubota T, Yokosawa N, Yokota S, Fujii N: C terminal Cys-rich region of mumps virus structural V protein correlates with block of interferon α and γ signal transduction pathway through decrease of STAT1-α. Biochem Biophys Res Commun 2001,283(1):255-259. 10.1006/bbrc.2001.4764PubMedView ArticleGoogle Scholar
- Ulane MC, Kentsis A, Cruz CD, Parisien JP, Schneider KL, Horvath CM: Composition and assembly of STAT-targeting ubiquitin ligase complexes: paramyxovirus V protein carboxyl terminus is an oligomerization domain. J Virol 2005,79(16):10180-10189. 10.1128/JVI.79.16.10180-10189.2005PubMedPubMed CentralView ArticleGoogle Scholar
- Andrejeva J, Poole E, Young DF, Goodbourn S, Randall RE: The p127 subunit (DDB1) of the UV-DNA damage repair binding protein is essential for the targeted degradation of STAT1 by the V protein of the paramyxovirus simian virus 5. J Virol 2002,76(22):11379-11386. 10.1128/JVI.76.22.11379-11386.2002PubMedPubMed CentralView ArticleGoogle Scholar
- Nishio M, Garcin D, Simonet V, Kolakofsky D: The carboxyl segment of the mumps virus V protein associates with Stat proteins in vitro via a tryptophan-rich motif. Virology 2002,300(1):92-99. 10.1006/viro.2002.1509PubMedView ArticleGoogle Scholar
- Nishio M, Tsurudome M, Ito M, Garcin D, Kolakofsky D, Ito Y: Identification of Paramyxovirus V protein residues essential for STAT protein degradation and promotion of virus replication. J Virol 2005,79(13):8591-8601. 10.1128/JVI.79.13.8591-8601.2005PubMedPubMed CentralView ArticleGoogle Scholar
- Sun M, Rothermel TA, Shuman L, Aligo JA, Xu S, Lin Y, Lamb RA, He B: Conserved cysteine-rich domain of paramyxovirus simian virus 5 V protein plays an important role in blocking apoptosis. J Virol 2004,78(10):5068-5078. 10.1128/JVI.78.10.5068-5078.2004PubMedPubMed CentralView ArticleGoogle Scholar
- Santos-López G, Cruz C, Pazos N, Vallejo V, Reyes-Leyva J, Tapia-Ramírez J: Two clones obtained from Urabe AM9 mumps virus vaccine differ in their replicative efficiency in neuroblastoma cells. Microbes Infect 2006,8(2):332-339. 10.1016/j.micinf.2005.06.031PubMedView ArticleGoogle Scholar
- Reyes-Leyva J, Baños R, Borraz-Arguello M, Santos-Lopez G, Alvarado G, Rosas N, Herrera I, Vallejo I, Tapia-Ramírez J: Amino acid change 335 E to K affects the sialic acid-binding affinity and neuraminidase activity level of Urabe AM9 mumps virus hemagglutinin-neuraminidase glycoprotein. Microbes Infect 2007,9(2):234-240. 10.1016/j.micinf.2006.11.011PubMedView ArticleGoogle Scholar
- Rosas-Murrieta N, Herrera-Camacho I, Vallejo-Ruiz V, Millán-Pérez-Peña L, Cruz C, Tapia-Ramírez J, Santos-López G, Reyes-Leyva J: Differential sensitivity to interferon influences the replication and transcription of Urabe AM9 mumps virus variants in nerve cells. Microbes Infect 2007,9(7):864-872. 10.1016/j.micinf.2007.03.005PubMedView ArticleGoogle Scholar
- Ulane CM, Rodríguez JJ, Parisien JP, Horvath CM: STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J Virol 2003,77(11):6385-6393. 10.1128/JVI.77.11.6385-6393.2003PubMedPubMed CentralView ArticleGoogle Scholar
- Li T, Chen X, Garbutt KC, Zhou P, Zheng N: Structure of DDB1 in complex with a paramyxovirus V protein: viral hijack of a propeller cluster in ubiquitin ligase. Cell 2006,124(1):105-117. 10.1016/j.cell.2005.10.033PubMedView ArticleGoogle Scholar
- Mao X, Ren Z, Parker G, Sondermann H, Pastorello M, Wang W, McMurray J, Demeler B, Darnell J, Chen X: Structural bases of unphosphorylated STAT1 association and receptor binding. Mol Cell 2005,17(6):761-771. 10.1016/j.molcel.2005.02.021PubMedView ArticleGoogle Scholar
- Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE, Kuriyan J: Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 1998,93(5):827-839. 10.1016/S0092-8674(00)81443-9PubMedView ArticleGoogle Scholar
- Young DF, Chatziandreou N, He B, Goodbourn S, Lamb RA, Randall RE: Single amino acid substitution in the v protein of simian virus 5 differentiates its ability to block interferon signaling in human and murine cells. J Virol 2001,75(7):3363-3370. 10.1128/JVI.75.7.3363-3370.2001PubMedPubMed CentralView ArticleGoogle Scholar
- Puri M, Lemon K, Duprex WP, Rima BK, Horvath CM: A point mutation, E95 D, in the mumps virus v protein disengages STAT3 targeting from STAT1 targeting. J Virol 2009,83(13):6347-6356. 10.1128/JVI.00596-09PubMedPubMed CentralView ArticleGoogle Scholar
- Young DF, Didcock L, Goodbourn S, Randall RE: Paramyxoviridade use distinct virus-specific mechanisms to circumvent the interferon response. Virology 2000,269(2):383-390. 10.1006/viro.2000.0240PubMedView ArticleGoogle Scholar
- Brown EG, Dimock K, Wright KE: The Urabe AM9 mumps vaccine is a mixture of viruses differing at amino acid 335 of the hemagglutinin-neuraminidase gene with one form associated with disease. J Infect Dis 1996,174(6):619-622.PubMedView ArticleGoogle Scholar
- Brown EG, Wright KE: Genetic studies on a mumps vaccine strain associated with meningitis. Rev Med Virol 1998,8(3):129-142. 10.1002/(SICI)1099-1654(199807/09)8:3<129::AID-RMV213>3.0.CO;2-ZPubMedView ArticleGoogle Scholar
- Yokosawa N, Kubota T, Fujii N: Poor induction of interferon-induced 2',5'-oligoadenylate synthetase (2-5 AS) in cells persistently infected with mumps virus is caused by decrease of STAT-1a. Arch Virol 1998,143(10):1985-1992. 10.1007/s007050050434PubMedView ArticleGoogle Scholar
- Fujii N, Yokosawa N, Shirakawa S: Suppression of interferon response gene expression in cells persistently infected with mumps virus, and restoration from its suppression by treatment with ribavirin. Virus Res 1999,65(2):175-185. 10.1016/S0168-1702(99)00114-8PubMedView ArticleGoogle Scholar
- Fagerlund R, Melen K, Kinnumen L, Julkumen I: Argine/lysine-rich NLSs mediate interactions between dimeric STATs and importin alpha 5. J Biol Chem 2002,277(33):30072-30078. 10.1074/jbc.M202943200PubMedView ArticleGoogle Scholar
- Andrejeva J, Young DF, Goodbourn S, Randall RE: Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: consequences for virus replication in the presence of alpha/beta and gamma interferons. J Virol 2002,756(5):2159-2167. 10.1128/jvi.76.5.2159-2167.2002View ArticleGoogle Scholar
- Didcock L, Young DF, Goodbourn F, Randall RE: The V protein of simian virus 5 inhibits interferon signalling by targeting STAT1 for proteasome-mediated degradation. J Virol 1999,73(12):9928-9933.PubMedPubMed CentralGoogle Scholar
- Arnold K, Bordoli L, Kopp J, Schwede T: The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling. Bioinformatics 2006,22(2):195-201. 10.1093/bioinformatics/bti770PubMedView ArticleGoogle Scholar
- Gibrat JF, Madej T, Bryant SH: Surprising similarities in structure comparison. Curr Opin Struct Biol 1996,6(3):377-385. 10.1016/S0959-440X(96)80058-3PubMedView ArticleGoogle Scholar
- Guex N, Peitsch MC: SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 1997,18(15):2714-2723. 10.1002/elps.1150181505PubMedView ArticleGoogle Scholar
- Laskowski RA, MacArthur MW, Moss DS, Thornton JM: PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst 1993, 26: 283-291. 10.1107/S0021889892009944View ArticleGoogle Scholar
- Wiederstein M, Sippl MJ: ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucl Acid Res 2007,35(Suppl 2):W407-W410. 10.1093/nar/gkm290View ArticleGoogle Scholar
- Combet C, Jambon M, Deléage G, Geourjon C: Geno3D: automatic comparative molecular modelling of protein. Bioinformatics 2002,18(1):213-214. 10.1093/bioinformatics/18.1.213PubMedView ArticleGoogle Scholar
- Maiti R, Van Domselaar GH, Zhang H, Wishart DS: SuperPose: a simple server for sophisticated structural superposition. Nucleic Acids Res 2004, (32 Web Server):W590-W594. 10.1093/nar/gkh477Google Scholar
- Tung CW, Ho SY: Computational identification of ubiquitylation sites from protein sequences. BMC Bioinform 2008, 9: 310-324. 10.1186/1471-2105-9-310View ArticleGoogle Scholar
- Ritchie DW, Kemp GJL: Protein docking using spherical polar Fourier correlations. Proteins 2000,39(2):178-194. 10.1002/(SICI)1097-0134(20000501)39:2<178::AID-PROT8>3.0.CO;2-6PubMedView ArticleGoogle Scholar
- Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ: PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 2005, (33 Web Server):W363-367. 10.1093/nar/gki481Google Scholar
- Mashiach E, Schneidman-Duhovny D, Andrusier N, Nussinov R, Wolfson HJ: FireDock: a web server for fast interaction refinement in molecular docking. Nucleic Acids Res 2008, (36 Web Server):W229-232. 10.1093/nar/gkn186Google Scholar
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