title: Functional and Structural Mimicry of Cellular Protein Kinase A Anchoring Proteins by a Viral Oncoprotein.
abstract: The oncoproteins of the small DNA tumor viruses interact with a plethora of cellular regulators to commandeer control of the infected cell. During infection, adenovirus E1A deregulates cAMP signalling and repurposes it for activation of viral gene expression. We show that E1A structurally and functionally mimics a cellular A-kinase anchoring protein (AKAP). E1A interacts with and relocalizes protein kinase A (PKA) to the nucleus, likely to virus replication centres, via an interaction with the regulatory subunits of PKA. Binding to PKA requires the N-terminus of E1A, which bears striking similarity to the amphipathic α-helical domain present in cellular AKAPs. E1A also targets the same docking-dimerization domain of PKA normally bound by cellular AKAPs. In addition, the AKAP like motif within E1A could restore PKA interaction to a cellular AKAP in which its normal interaction motif was deleted. During infection, E1A successfully competes with endogenous cellular AKAPs for PKA interaction. E1A's role as a viral AKAP contributes to viral transcription, protein expression and progeny production. These data establish HAdV E1A as the first known viral AKAP. This represents a unique example of viral subversion of a crucial cellular regulatory pathway via structural mimicry of the PKA interaction domain of cellular AKAPs.
authors.affiliation: Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Cason R
authors.initials: CR
authors.lastname: King
authors.affiliation: Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cohen
authors.affiliation: Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Fonseca
authors.affiliation: Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Brennan S
authors.initials: BS
authors.lastname: Dirk
authors.affiliation: Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Dikeakos
authors.affiliation: Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.|Department of Oncology, University of Western Ontario, London, Ontario, Canada.|London Regional Cancer Program and Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000378:metabolism*; D000256:Adenoviridae / Q000737:chemistry / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D007091:Image Processing, Computer-Assisted; D047468:Immunoprecipitation; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054758:A Kinase Anchor Proteins; D017500:Adenovirus E1A Proteins; D017868:Cyclic AMP-Dependent Protein Kinases