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Animal: DNA Viruses |
Department of Microbiology, University of Otago, PO Box 56, Dunedin, New Zealand1
Dipartimento di Sanità Pubblica Veterinaria e Patologia Animale, Università degli Studi di Bologna, Bologna, Italy2
Moredun Research Institute, Edinburgh, UK3
Institute of Immunology, Federal Research Centre for Virus Diseases of Animals, Tübingen, Germany4
Author for correspondence: Andrew Mercer. Fax +64 3 4797744. e-mail andy.mercer{at}stonebow.otago.ac.nz
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Introduction |
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). Several reports have described prominent vascular changes associated with lesions caused by Orf virus. The discovery that Orf virus encodes a homologue of mammalian vascular endothelial growth factor (VEGF-A) suggested a possible explanation for these observations (Lyttle et al., 1994 ). VEGF-A is a mitogen specific for vascular endothelial cells, a potent inducer of vascular permeability and plays a critical role in the formation of new blood vessels during both vasculogenesis and angiogenesis (Ferrara, 1999 ; Robinson & Stringer, 2001 ; Stacker & Achen, 1999 ). Disruption of the VEGF-A gene results in embryonic lethality because of failed development of the vasculature. VEGF-A also plays an important role in the angiogenesis associated with tumour formation and a number of other pathological conditions. In addition to a series of isoforms of VEGF-A, the VEGF family of growth factors includes VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF). All are secreted homodimeric glycoproteins that share 30 to 45% amino acid sequence identity. All contain a VEGF homology domain (VHD) that includes eight cysteine residues involved in intra-or inter-chain disulphide bonds and are hence members of the cystine-knot family of proteins. The VEGF family are ligands for a set of tyrosine kinase receptors. VEGF-A binds and activates VEGF receptor 1 (VEGFR-1) (Flt1) and VEGFR-2 (Flk1/KDR) but not VEGFR-3 (Flt4). PlGF and VEGF-B bind only VEGFR-1 while VEGF-C and VEGF-D bind both VEGFR-2 and VEGFR-3 but not VEGFR-1. The role of each receptor-ligand interaction remains to be precisely defined but in general terms it appears that VEGFR-1 plays a role in vascular endothelial differentiation and migration, VEGFR-2 is the main signal-transducing VEGF receptor for mitogenesis of endothelial cells and VEGFR-3 is involved in angiogenesis of the lymphatic vasculature.
We and others have recently demonstrated that VEGF encoded by Orf virus is a cystine-knot homodimer that has some of the functional features of mammalian VEGF (Meyer et al., 1999 ; Ogawa et al., 1998 ; Wise et al., 1999 ). The purified factor derived from Orf virus strain NZ2 was able to stimulate proliferation of vascular endothelial cells, promote vascular permeability and was shown to bind VEGFR-2 but not VEGFR-1 or VEGFR-3. As such the viral VEGF forms a new member of the VEGF family of molecules with a unique profile of receptor recognition. We have also shown that infection of sheep with a recombinant Orf virus in which the viral VEGF gene was partially deleted resulted in lesions that lacked the extensive dermal vascularization seen in wild-type infections (Savory et al., 2000 ). No other virus has been reported to encode a form of VEGF.
The original report of a possible viral VEGF described two independent New Zealand isolates of Orf virus (Lyttle et al., 1994 ). The isolates (NZ2 and NZ7) encode predicted peptides of similar size with similar levels of sequence relatedness to mammalian VEGFs and both peptides have been shown to have similar VEGF-like activities (Ogawa et al., 1998 ; Wise et al., 1999 ). However, the two viral genes are unexpectedly different from each other sharing only 41·1% predicted amino acid sequence identity. This raised the possibility that further variants of VEGF are encoded by other isolates of Orf virus. In order to investigate the sequence variation and distribution of VEGF genes of Orf virus we examined a selection of isolates from diverse sources.
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Viruses and cells. ). NZ7 was provided by Coopers Animal Health New Zealand Ltd. With the exception of NZ2, NZ7 and NZ10, the samples analysed were derived directly from clinical cases of contagious ecthyma in lambs. Strains NZ2, NZ7 and NZ10 were plaque-purified in bovine testis cells and then inoculated onto sheep. Scabs that formed were recovered and used as the source of viral DNA (Mercer et al., 1987 ). Strain NZh1 was recovered in Dunedin, New Zealand from a naturally infected adult woman. Strain Acsl is a contagious ecthyma vaccine originating from Commonwealth Serum Laboratories, Australia. MRI1 and MRI3 are samples derived from naturally infected sheep in South Glamorgan, Wales and Inverness, Scotland, respectively, and have been passaged once on sheep (Gilray et al., 1998 ). MRIsc is a Scottish reference strain maintained on sheep and which has not been adapted to grow in cell culture (elsewhere referred to as MRI scab), while MRI11 is a Scottish reference strain maintained by passage in primary bovine testis or foetal lamb muscle and elsewhere referred to as MRI orf11 (McInnes et al., 2001 ). Strains ITtor, ITC2, IT7, IT90, IT19 and IT20 are from Italy. IT7, IT19 and IT20 are scab samples from naturally infected sheep. The other three have been adapted to grow in ovine testis cells. IT90 and ITtor are derived from samples taken from chamois while ITC2 is from sheep. Strains D15, D23, D47 and D1701 were recovered from naturally infected sheep or goat (D47) in Germany and have been propagated in cultured bovine foetal lung cells or BK-KL3A cells. D1701 is a highly attenuated strain derived after multiple cell culture passages (Cottone et al., 1998 ).
DNA manipulations.
Virus was purified and DNA recovered as previously described (Mercer et al., 1987 ). The primer pairs used in PCRs were derived from the first and last six codons of D1701 VEGF (Meyer et al., 1999 ), NZ2 VEGF or NZ7 VEGF (Lyttle et al., 1994 ). PCRs were performed using 30 cycles of 50 °C 20 s, 72 °C 20 s and 95 °C 20 s. The DNA sequences of the PCR products were either determined directly or the amplified products were cloned into plasmid vectors and the sequence determined from at least five different clones. Double-stranded DNA templates were prepared and sequenced by procedures recommended by Applied Biosystems Inc. (ABI). The products of sequencing reactions were analysed with an ABI model 373A sequencing system. Assembly and analysis of nucleotide sequence was conducted using programs of the DNASTAR package. Phylogenetic analysis of aligned sequences was conducted using programs of the PHYLIP package version 3·6 (Felsenstein, 1989 ); genetic distances were calculated using PROTDIST (Jones–Taylor–Thornton matrix) and phylogenetic trees constructed by the neighbour-joining method (NEIGHBOR).
Prediction of the tertiary structure of the VEGF-variants of Orf virus.
The structure of the VEGF-variants of Orf virus were modelled using SWISSMODEL and the SWISSPDBVIEWER protein modelling program (version 3.5; Guex & Peitsch, 1997 ), which are both available from the ExPASy website (http://www.expasy.ch/spdbv). The sequences of the variants were aligned using SWISSMODEL against protein subunits A and B of human VEGF-A (Muller et al., 1997a ) (PDB identifier, 2VPF). The Iterative Magic Fit function was used for energy minimization and the alignments were manually optimized. Ramachandran plots for the viral VEGF models, VEGF-A and PlGF, were compared to determine if the viral models contained residues that did not conform to acceptable 
and/or 
angles.
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Results and Discussion |
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The majority of isolates tested (18) encoded VEGF-like genes with sequences related to that of NZ2 VEGF. An alignment of the predicted amino acid sequences of these NZ2-like VEGFs is shown in Fig. 1 along with the established sequences for NZ2, D1701 and NZ7. The nucleotide and amino acid relationships between the NZ2-like VEGFs are listed in Table 1. In only one case (NZ9) was the VEGF nucleotide sequence identical to that of NZ2. The NZ2-like VEGF genes were on average 93·5% identical to NZ2 VEGF in nucleotide sequence. In all 190 combinations of the 20 NZ2-like VEGFs, there were only eight combinations that were identical at the amino acid level and the average amino acid identity between pairs of sequences was 86·1% with a standard deviation of 7·6.
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). However, the majority of our data is derived from samples taken directly from naturally infected animals (MRI1, MRI3, IT7, IT19, IT20, NZ9, NZ12, NZ52, NZ66 and NZ180). Strain MRI11 has been adapted to grow in cultured cells and this is the most-variant of the NZ2-like VEGFs, with average sequence identities to the other clones of 76·99±0·77% (nucleotide) and 71·84±1·53% (amino acid). However, the VEGFs derived from other strains known to have been repeatedly passaged in cultured cells (D1701 and ITC2) are no more variant than scab-derived samples. Furthermore, a passaged derivative of strain NZ2 that is known to have undergone substantial genomic alterations (Fleming et al., 1995 ) carries a VEGF gene identical in nucleotide sequence to that of the parent strain (unpublished). Alignment of DNA sequences revealed only 31·9% sequence identity for MRI11 and NZ7 but 73·1% identity for MRI11 and NZ2, confirming that, despite its extreme variation, MRI11 is correctly included in the NZ2-like group. Conditioned medium from MRI11-infected cells showed activity in a VEGFR-2 bioassay (Wise et al., 1999 ), suggesting that the MRI11-encoded VEGF is biologically active (unpublished).
The inclusion of MRI11 in the NZ2-like group is also supported by the phylogenetic analysis shown in Fig. 2. This phylogenetic tree illustrates the relationships between the viral VEGFs and demonstrates the clear separation of NZ2-like and NZ7-like VEGFs. It also reveals some evidence of geographical clustering with peptides of identical (ITtor, ITC2 and IT90, NZ10, Acsl and NZh1) or very similar sequences (IT19 and IT20, and NZ2, NZ66 and NZ9) likely to have come from the same country. However, the differences between MRI1 and MRI3, between NZ2 and NZ12 and between IT90 and IT20 clearly indicate that more than one clone is present in each country. The amino acid sequence identity between the human derived clone (NZh1) and NZ10 suggests that there is not a specific clone infecting humans rather than sheep and is consistent with the evidence that human infection by Orf virus is sourced from sheep. Similarly, the sequence identity between IT90, ITtor and ITC2 suggests that the same clones of Orf virus infect both sheep and chamois.
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; Shchelkunov et al., 1998 ; Twardzik et al., 1985 ). This factor is not encoded by Orf virus but, like the VEGF of Orf virus, it is a secreted cytokine that is a ligand for membrane-bound receptors and stimulates the replication of target cells. Amongst the epidermal growth factors from four strains of vaccinia virus (Copenhagen, WR, Ankara and Tian Tan; accession nos P20494, P01136, AAB96482 and AAF33857 respectively) the extent of amino acid sequence identity ranges from 91·4 to 98·9% with an average of 95·5%. Examination of the data for three isolates of variola virus (Bangladesh 1975, India 1967 and Garcia 1966; accession nos AAA60749, P33804, and C72150 respectively) showed amino acid sequence identity ranging from 97·1 to 99·3%. Comparison of the vaccinia virus factors with the variola virus factors revealed that the amino acid sequence identity between species ranged from 82·9 to 88·6%. A similar range was observed between these sequences and the predicted protein of a third species of orthopoxvirus, cowpox virus. These comparisons illustrate that the extent of sequence variation seen in VEGFs from Orf virus is unusually high and is more similar to the variation seen in homologous proteins from different species of the same genus of poxviruses rather than between independent isolates of the same species.
The sequence variation seen in VEGF genes of Orf virus is not a general feature of genes of this virus. For example, Orf virus also encodes a homologue of the cytokine interleukin-10 (IL-10) (Fleming et al., 2000 ). The predicted amino acid sequences for the IL-10s encoded by Orf virus strains NZ2 and NZ7 differ by only 2·7%. Two further examples are provided by an interferon resistance element and an inhibitor of GM-CSF encoded by Orf virus. Inter-strain amino acid sequence variation for both these elements is less than 3% (Deane et al., 2000 ; McInnes et al., 1998 ).
Nor is the sequence variation seen in VEGF genes of Orf virus likely to reflect accelerated genetic drift of silent genes. In all isolates key functional motifs such as the cystine-knot motif are conserved. Furthermore, in addition to the characterized activity of the VEGFs encoded by strains NZ2, D1701 and NZ7 (Meyer et al., 1999 ; Ogawa et al., 1998 ; Wise et al., 1999 ), we detected VEGF-like activity in conditioned medium of cells infected with each of strains D15, D23, D47 or MRI11 (not shown).
Receptor-binding motifs
Members of the VEGF family share a VEGF homology domain (VHD) containing eight cysteine residues that form the cystine-knot motif and link the subunits of the anti-parallel homodimer. Despite the sequence variation detailed above, all eight cysteines are conserved in all of the VEGF-variants of Orf virus (Fig. 1
). Also conserved in each of the VEGFs of Orf virus are a potential signal sequence and potential N- and O-linked glycosylation sites (Fig. 1). A threonine/proline-rich motif seen in the C terminus of VEGFs encoded by both NZ2 and NZ7 but not seen in mammalian VEGFs is retained in all viral VEGFs (Fig. 1).
The conservation of structure within the VEGF family of growth factors suggests that residues important in mediating the binding of different members to their receptors are likely to be conserved. We aligned representatives of the VEGF family with the viral VEGFs and looked for any correlation with the ability to bind VEGFR-1 or VEGFR-2 (Fig. 3). We focused initially on residues that have been implicated in mediating binding to these receptors.
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; Li et al., 2000 ). Ala substitutions have implicated residues Phe-17, Tyr-21, Ile-43, Ile-46, Glu-64, Gln-79, Ile-83 and Pro-85 as playing important roles in the binding of VEGF-A to VEGFR-2 (Li et al., 2000 ; Muller et al., 1997a ). Comparisons of these positions in VEGF family members, including the viral VEGFs, revealed little evidence of correlations with the ability or inability to recognize VEGFR-1 or VEGFR-2 (Fig. 3). Ile-43 of VEGF-A is conserved in VEGF-As of 12 mammalian species and is matched by a Val at this position in four species of VEGF-B and three species of PlGF-1 (Fig. 3). These factors all recognize VEGFR-1, whereas in VEGF-C (four species) and in VEGF-D (three species), which do not recognize VEGFR-1, a Thr is conserved at this position. Furthermore, all 24 isolates of Orf virus (both NZ2 and NZ7-like) also carry a Thr at this position. Despite these correlations, an Ala substitution of Ile-43 of VEGF-A has been shown to reduce binding to VEGFR-1 only modestly (Li et al., 2000 ) and has a greater effect on the recognition of VEGFR-2 (Li et al., 2000 ; Muller et al., 1997b ).
Correlations with the ability to recognize specific VEGF receptors were detected in other residues. Ser-50 of VEGF-A is retained in all factors that recognize VEGFR-1 but is not present in any of the factors that do not recognize this receptor (Fig. 3). The NZ2-like viral VEGFs along with VEGF-C and VEGF-D generally have a Pro at this position. Mutational analysis of this residue has not been reported.
A strong correlation is apparent between binding of VEGFR-2 and the presence of Asn at a position equivalent to Asn-62 of VEGF-A. This residue is conserved in 11 of 12 species of VEGF-A, four species of VEGF-C, three species of VEGF-D and all 24 viral isolates. In contrast this residue is not found in PlGF-1 (three species have Gly) or VEGF-B (4 species have Pro) which do not recognize VEGFR-2. Crystal structure determination of VEGF-A has shown that Asn-62 is an accessible residue on the receptor-binding face of the ligand (Muller et al., 1997a ). However substitution of this residue by Ala reduced the relative affinity of VEGF-A for VEGFR-2 only modestly (Muller et al., 1997b ).
Structural modelling
Predicted structures of the VEGF-variants of Orf virus were determined by comparison to the solved crystal structure of subunits A and B of VEGF-A. Despite only moderate sequence identity, the structures predicted for the viral VEGF monomers are very similar both to each other and to the structure determined by X-ray crystallography for VEGF-A (Fig. 4). They conserve the central anti-parallel, four-stranded 
sheet and two 
-helical segments. With the exception of the VEGFs encoded by Orf virus strains NZ7 (ORFVNZ7VEGF) and MRI11 (ORFVMRI11VEGF), the modelling program we used did not detect interruptions in the fourth and fifth sheets so as to generate 4/5 and 6/7 as determined for published structures of VEGF (Muller et al., 1997a ). However, for greater clarity we have retained the published nomenclature of seven sheets. The orientations of the cysteines forming the intra-chain disulphide bonds responsible for the cystine-knot motif are maintained in the viral VEGFs (Muller et al., 1997a ). Also maintained is the three-stranded anti-parallel sheet (2, 5 and 6) at the opposite end of the monomer to the cystine-knot and shown to be part of the receptor-binding face of VEGF-A (Muller et al., 1997a , b ). The viral VEGF monomers also contain the three variable loop regions, connecting strands 1 to 3, 3 to 4 and 5 to 6. The third loop region is extended by three and five amino acids in ORFVMRI11VEGF and ORFVNZ7VEGF, respectively.
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VEGF-A dimerizes in an anti-parallel, side-by-side fashion, with the monomers being covalently linked by two symmetrical disulphide bonds between Cys-51 and Cys-60. These cysteine residues are also conserved in the viral VEGFs, some of which have been shown to act as dimers (Meyer et al., 1999 ; Ogawa et al., 1998 ; Wise et al., 1999 ). The viral VEGFs were therefore predicted to dimerize in a similar fashion to VEGF-A and modelling revealed dimeric structures very similar to that of VEGF-A (Fig. 5).
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; Muller et al., 1997a ; Wiesmann et al., 1997 ). The binding sites for VEGFR-1 and VEGFR-2 appear to overlap and each extends across the subunit interface. Fig. 6 shows surface rendering representations of VEGF-A, ORFVNZ2VEGF and ORFVNZ7VEGF in two orientations. Residues which make up the receptor-binding face are shaded in a dark grey. This face is built from strands 2, 5 and 6 from one monomer and helix 1, the 3-4 loop and the 7 strand from the other monomer (Muller et al., 1997a ; Wiesmann et al., 1997 ). In addition, some residues of VEGF-A are coloured to indicate that they have been implicated in mediating the binding of VEGF-A to VEGFR-1 (yellow), VEGFR-2 (blue) or both receptors (green) (Keyt et al., 1996 ; Li et al., 2000 ; Muller et al., 1997b ). Where these residues are conserved in ORFVNZ2VEGF or ORFVNZ7VEGF they are coloured in the same manner. The models shown in Fig. 6 confirm the structural similarities between the viral VEGFs and VEGF-A, including the location of the receptor-binding face. Furthermore, where residues implicated in VEGFR-binding are conserved in the viral factors, they occupy similar three-dimensional locations. However, the rather small number of these residues conserved in the viral VEGFs is clearly illustrated (Fig. 6).
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). It has been proposed that domain 2 of VEGFR-1 binds to the receptor-binding ‘end’ of VEGF-A while the region linking domains 2 and 3 of the receptor occupies a 6·5 
wide groove between the VEGF-A monomers and thereby positions domain 3 in contact with the ‘bottom’ face of VEGF-A (Wiesmann et al., 1997 ). The grooves at each end of the VEGF-A dimer connect the ends of the dimer to the flat membrane-facing side (‘bottom’) of VEGF-A. The walls of the groove in VEGF-A are formed by Asp-63 and Glu-64 on one side and Ile-43, Ile-46 and Phe-36 on the other side, while the floor is formed by Asp-34 and Ser-50 (Iyer et al., 2001 ; Wiesmann et al., 1997 ). Fig. 7 shows a surface rendering representation of VEGF-A in which the residues forming the surfaces of the groove have been shaded. The expanded view shows the groove more clearly with one side of the groove represented by Glu-64, the other side by Ile-46 and the floor by Ser-50. Matched representations of ORFVNZ2VEGF and ORFVNZ7VEGF are also shown. In the viral VEGFs, residues occupying the same predicted locations (see Fig. 3) as those forming the walls of the groove in VEGF-A are also shaded and marked. It can be seen that the strong interaction between residues Glu-74 and Arg-56 of ORFVNZ2VEGF appears to block the opening to the groove. This effect is less apparent between the equivalent residues (Asp-81 and Gln-63) of ORFVNZ7VEGF but the presence of Arg-67 in place of Ser-50 of VEGF-A has the effect of raising the floor and filling the groove. This effect can also be seen in the end-on view of ORFVNZ2VEGF shown in Fig. 6. It is intriguing that in the correlations discussed above the presence of Ser-50 was unusual in that it showed a strong correlation with the ability to recognize VEGFR-1 (Fig. 3). These models raise the possibility that the inability of the viral VEGFs to bind VEGFR-1 is related to their lack of a groove able to bind effectively the domain 2–3 linker region of the receptor. Structural analysis of PlGF, which recognizes only VEGFR-1, has shown that the groove seen in VEGF-A is conserved in PlGF (Iyer et al., 2001 ).
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). The sequence variations reported here might reflect genetic drift of the recently acquired gene although the rate of drift seems greater than generally seen in poxvirus genes. This explanation does not account for the very substantial difference between the NZ2-like and the NZ7-like VEGFs. It is possible that the NZ7-like VEGF was acquired by Orf virus independently of the NZ2 acquisition event and from a different source. An as yet unidentified member of the mammalian VEGF family is one possible source. An alternative source is another parapoxvirus. We have preliminary evidence of VEGF-like activity expressed by cells infected with other species of parapoxvirus (unpublished).
Recombination during co-infection by Orf virus and another species of parapoxvirus might have resulted in the transfer of the NZ7-like VEGF into Orf virus. The minimal variation seen in NZ7-like sequences might suggest that such an event happened recently. Despite the surprising extent of sequence variation among the viral VEGFs, key motifs of structural and functional importance are conserved. These include the eight cysteines of the cystine-knot motif and potential glycosylation sites. A sequence motif rich in threonine and proline seen in the C terminus of the VEGFs encoded by both NZ2 and NZ7 is unique to the viral VEGFs (Lyttle et al., 1994 ) and is retained in all isolates. Determining the functional significance of the sequence variations reported here will require further examination.
This collection of natural variants of VEGF provides opportunities to examine the importance of specific sequence motifs in the various activities of VEGF. The precise nature of the interaction between the viral VEGFs and VEGFR-2 is clearly of interest. It is intriguing that, despite the lack of retention of residues implicated as being critical in the binding of VEGF-A to VEGFR-2 and the lack of conservation of residues between NZ2- and NZ7-like viruses, both NZ2- and NZ7-like VEGFs have been shown to bind and activate VEGFR-2 (Meyer et al., 1999 ; Ogawa et al., 1998 ; Wise et al., 1999 ). This indicates that the viral VEGFs binding site(s) may differ, or that considerable variability can be tolerated while still maintaining the ability to bind VEGFR-2. We hypothesize that the failure of viral VEGFs to bind VEGFR-1 may relate to the absence in these factors of a groove able to accept the VEGFR-1 domain 2–3 linker. Site-directed mutagenesis of the relevant residues will be required to test this hypothesis.
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Acknowledgments |
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References |
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Received 12 April 2002;
accepted 10 July 2002.
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 S. Cebe-Suarez, F. S. Grunewald, R. Jaussi, X. Li, L. Claesson-Welsh, D. Spillmann, A. A. Mercer, A. E. Prota, and K. Ballmer-Hofer Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR FASEB J, August 1, 2008; 22(8): 3078 - 3086. [Abstract] [Full Text] [PDF]
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 Z.-L. Wang, X.-P. Xu, B.-L. He, S.-P. Weng, J. Xiao, L. Wang, T. Lin, X. Liu, Q. Wang, X.-Q. Yu, et al. Infectious Spleen and Kidney Necrosis Virus ORF48R Functions as a New Viral Vascular Endothelial Growth Factor J. Virol., May 1, 2008; 82(9): 4371 - 4383. [Abstract] [Full Text] [PDF]
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 M. K. Inder, N. Ueda, A. A. Mercer, S. B. Fleming, and L. M. Wise Bovine papular stomatitis virus encodes a functionally distinct VEGF that binds both VEGFR-1 and VEGFR-2 J. Gen. Virol., March 1, 2007; 88(3): 781 - 791. [Abstract] [Full Text] [PDF]
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M. Pieren, A. E. Prota, C. Ruch, D. Kostrewa, A. Wagner, K. Biedermann, F. K. Winkler, and K. Ballmer-Hofer Crystal Structure of the Orf Virus NZ2 Variant of Vascular Endothelial Growth Factor-E: IMPLICATIONS FOR RECEPTOR SPECIFICITY J. Biol. Chem., July 14, 2006; 281(28): 19578 - 19587. [Abstract] [Full Text] [PDF]
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G. Delhon, E. R. Tulman, C. L. Afonso, Z. Lu, A. de la Concha-Bermejillo, H. D. Lehmkuhl, M. E. Piccone, G. F. Kutish, and D. L. Rock Genomes of the Parapoxviruses Orf Virus and Bovine Papular Stomatitis Virus J. Virol., January 1, 2004; 78(1): 168 - 177. [Abstract] [Full Text] [PDF]
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K. Thomas, D. M. Tompkins, A. W. Sainsbury, A. R. Wood, R. Dalziel, P. F. Nettleton, and C. J. McInnes A novel poxvirus lethal to red squirrels (Sciurus vulgaris) J. Gen. Virol., December 1, 2003; 84(12): 3337 - 3341. [Abstract] [Full Text] [PDF]
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L. M. Wise, N. Ueda, N. H. Dryden, S. B. Fleming, C. Caesar, S. Roufail, M. G. Achen, S. A. Stacker, and A. A. Mercer Viral Vascular Endothelial Growth Factors Vary Extensively in Amino Acid Sequence, Receptor-binding Specificities, and the Ability to Induce Vascular Permeability yet Are Uniformly Active Mitogens J. Biol. Chem., September 26, 2003; 278(39): 38004 - 38014. [Abstract] [Full Text] [PDF]
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H.-J. Rziha, B. Bauer, K.-H. Adam, M. Rottgen, R. Cottone, M. Henkel, C. Dehio, and M. Buttner Relatedness and heterogeneity at the near-terminal end of the genome of a parapoxvirus bovis 1 strain (B177) compared with parapoxvirus ovis (Orf virus) J. Gen. Virol., May 1, 2003; 84(5): 1111 - 1116. [Abstract] [Full Text] [PDF]
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