title: Degenerate cysteine patterns mediate two redox sensing mechanisms in the papillomavirus E7 oncoprotein.
abstract: Infection with oncogenic human papillomavirus induces deregulation of cellular redox homeostasis. Virus replication and papillomavirus-induced cell transformation require persistent expression of viral oncoproteins E7 and E6 that must retain their functionality in a persistent oxidative environment. Here, we dissected the molecular mechanisms by which E7 oncoprotein can sense and manage the potentially harmful oxidative environment of the papillomavirus-infected cell. The carboxy terminal domain of E7 protein from most of the 79 papillomavirus viral types of alpha genus, which encloses all the tumorigenic viral types, is a cysteine rich domain that contains two classes of cysteines: strictly conserved low reactive Zn+2binding and degenerate reactive cysteine residues that can sense reactive oxygen species (ROS). Based on experimental data obtained from E7 proteins from the prototypical viral types 16, 18 and 11, we identified a couple of low pKa nucleophilic cysteines that can form a disulfide bridge upon the exposure to ROS and regulate the cytoplasm to nucleus transport. From sequence analysis and phylogenetic reconstruction of redox sensing states we propose that reactive cysteine acquisition through evolution leads to three separate E7s protein families that differ in the ROS sensing mechanism: non ROS-sensitive E7s; ROS-sensitive E7s using only a single or multiple reactive cysteine sensing mechanisms and ROS-sensitive E7s using a reactive-resolutive cysteine couple sensing mechanism.
authors.affiliation: Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Camporeale
authors.affiliation: ULB-Neuroscience Institute, Universite Libre de Bruxelles, Bruxelles, Belgium.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Lorenzo
authors.affiliation: RNA Cell Biology Laboratory, Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Thomas
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir-CONICET and IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Salvatierra
authors.affiliation: Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Borkosky
authors.affiliation: Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: Marikena G
authors.initials: MG
authors.lastname: Risso
authors.affiliation: Protein Physiology Laboratory, Universidad de Buenos Aires, CONICET, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.
authors.forename: Ignacio E
authors.initials: IE
authors.lastname: Sánchez
authors.affiliation: Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires, Argentina. Electronic address: gpg@leloir.org.ar.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: de Prat Gay
authors.affiliation: Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires, Argentina. Electronic address: lalonso@leloir.org.ar.
authors.forename: Leonardo G
authors.initials: LG
authors.lastname: Alonso
mesh_terms: D002466:Cell Nucleolus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D004220:Disulfides; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D003545:Cysteine