title: Poxvirus ankyrin repeat proteins are a unique class of F-box proteins that associate with cellular SCF1 ubiquitin ligase complexes.
abstract: F-box proteins direct the degradation of an extensive range of proteins via the ubiquitin-proteasome system. Members of this large family of proteins are typically bipartite. They recruit specific substrates through a substrate-binding domain and, via the F-box, link these to core components of a major class of ubiquitin ligases (SCF1). F-box proteins thus determine the specificity of SCF1-mediated ubiquitination. F-box-like motifs were recently detected in poxvirus ankyrin repeat (ANK) proteins but clear compositional differences to typical F-box proteins raise questions regarding the classification and function of the motif. Here we show that all five ANK proteins of a representative poxvirus, Orf virus, interact in vivo with core components of the SCF1 ubiquitin ligase complex. Interaction is dependent on the poxviral F-box-like motif and the adaptor subunit of the complex (SKP1). The viral protein does not block enzymatic activity of the complex. These observations identify the poxviral motif as a functional F-box. They also identify a new class of F-box that in contrast to cellular counterparts is truncated, has an extreme C-terminal location and is paired with an ANK protein-binding domain. ANK proteins constitute the largest family of poxviral proteins but their function and the significance of their abundance have remained an enigma. We propose that poxviruses use these unique ANK/F-box proteins to dictate target specificity to SCF1 ubiquitin ligases and thereby exploit the cell's ubiquitin-proteasome machinery.
authors.affiliation: Department of Microbiology and Immunology, University of Otago, PO Box 56, Dunedin 9016, New Zealand.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sonnberg
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Seet
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fleming
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Mercer
mesh_terms: D000595:Amino Acid Sequence; D017089:Ankyrin Repeat / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D002853:Chromatography, Liquid; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D009923:Orf virus / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D053719:Tandem Mass Spectrometry; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; D044843:SKP Cullin F-Box Protein Ligases