title: Vascular endothelial growth factors encoded by Orf virus show surprising sequence variation but have a conserved, functionally relevant structure.
abstract: The first report of a vascular endothelial growth factor (VEGF)-like gene in Orf virus included the surprising observation that the genes from two isolates (NZ2 and NZ7) shared only 41.1% amino acid sequence identity. We have examined this sequence disparity by determining the VEGF gene sequence of 21 isolates of Orf virus derived from diverse sources. Most isolates carried NZ2-like VEGF genes but their predicted amino acid sequences varied by up to 30.8% with an average amino acid identity between pairs of NZ2-like sequences of 86.1%. This high rate of sequence variation is more similar to interspecies than intraspecies variability. In contrast, only three isolates carried an NZ7-like VEGF gene and these varied from the NZ7 sequence by no more than a single nucleotide. The VEGF family are ligands for a set of tyrosine kinase receptors. The viral VEGFs are unique among the family in that they recognize VEGF receptor 2 (VEGFR-2) but not VEGFR-1 or VEGFR-3. Comparisons of the viral VEGFs with other family members revealed some correlations between conserved residues and the ability to recognize specific VEGF receptors. Despite the sequence variations, structural predictions for the viral VEGFs were very similar to each other and to the structure determined by X-ray crystallography for human VEGF-A. Structural modelling also revealed that a groove seen in the VEGF-A homodimer and believed to play a role in its binding to VEGFR-1 is blocked in the viral VEGFs. This may contribute to the inability of the viral VEGFs to bind VEGFR-1.
authors.affiliation: Department of Microbiology, University of Otago, PO Box 56, Dunedin, New Zealand1.
authors.forename: A A
authors.initials: AA
authors.lastname: Mercer
authors.affiliation: Department of Microbiology, University of Otago, PO Box 56, Dunedin, New Zealand1.
authors.forename: L M
authors.initials: LM
authors.lastname: Wise
authors.affiliation: Dipartimento di Sanità Pubblica Veterinaria e Patologia Animale, Università degli Studi di Bologna, Bologna, Italy2.
authors.forename: A
authors.initials: A
authors.lastname: Scagliarini
authors.affiliation: Moredun Research Institute, Edinburgh, UK3.
authors.forename: C J
authors.initials: CJ
authors.lastname: McInnes
authors.affiliation: Institute of Immunology, Federal Research Centre for Virus Diseases of Animals, Tübingen, Germany4.
authors.forename: M
authors.initials: M
authors.lastname: Büttner
authors.affiliation: Institute of Immunology, Federal Research Centre for Virus Diseases of Animals, Tübingen, Germany4.
authors.forename: H J
authors.initials: HJ
authors.lastname: Rziha
authors.affiliation: Department of Microbiology, University of Otago, PO Box 56, Dunedin, New Zealand1.
authors.forename: C A
authors.initials: CA
authors.lastname: McCaughan
authors.affiliation: Department of Microbiology, University of Otago, PO Box 56, Dunedin, New Zealand1.
authors.forename: S B
authors.initials: SB
authors.lastname: Fleming
authors.affiliation: Department of Microbiology, University of Otago, PO Box 56, Dunedin, New Zealand1.
authors.forename: N
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Moredun Research Institute, Edinburgh, UK3.
authors.forename: P F
authors.initials: PF
authors.lastname: Nettleton
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002460:Cell Line; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D016228:Endothelial Growth Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009923:Orf virus / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012756:Sheep; D012757:Sheep Diseases / Q000821:virology*; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D042442:Vascular Endothelial Growth Factors; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014764:Viral Proteins; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3