title: Transcription activator structure reveals redox control of a replication initiation reaction.
abstract: Redox changes are one of the factors that influence cell-cycle progression and that control the processes of cellular proliferation, differentiation, senescence and apoptosis. Proteins regulated through redox-sensitive cysteines have been characterized but specific 'sulphydryl switches' in replication proteins remain to be identified. In bovine papillomavirus type-1, DNA replication begins when the viral transcription factor E2 recruits the viral initiator protein E1 to the origin of DNA replication (ori). Here we show that a novel dimerization interface in the E2 transcription activation domain is stabilized by a disulphide bond. Oxidative cross-linking via Cys57 sequesters the interaction surface between E1 and E2, preventing pre-initiation and replication initiation complex formation. Our data demonstrate that as well as a mechanism for regulating DNA binding, redox reactions can control replication by modulating the tertiary structure of critical protein factors using a specific redox sensor.
authors.affiliation: Institute for Cancer Studies, University of Sheffield, Beech Hill Rd, Sheffield, S10 2RX, UK. c.m.sanders@sheffield.ac.uk
authors.forename: Cyril M
authors.initials: CM
authors.lastname: Sanders
authors.forename: Dmytro
authors.initials: D
authors.lastname: Sizov
authors.forename: Philippa R
authors.initials: PR
authors.lastname: Seavers
authors.forename: Miguel
authors.initials: M
authors.lastname: Ortiz-Lombardía
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Antson
mesh_terms: D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D008958:Models, Molecular; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D018741:Replication Origin; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C069814:E1 protein, Bovine papillomavirus; C051550:E2 protein, Bovine papillomavirus; D015534:Trans-Activators; D014764:Viral Proteins; D004247:DNA; D003545:Cysteine