Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles
The E7 protein from high-risk human papillomavirus is essential for cell transformation in cervical, oropharyngeal, and other HPV-related cancers, mainly through the inactivation of the retinoblastoma (Rb) tumor suppressor. Its high cysteine content (∼7%) and the observation that HPV-transformed cel...
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2014
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v53_n10_p1680_Chemes http://hdl.handle.net/20.500.12110/paper_00062960_v53_n10_p1680_Chemes |
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paper:paper_00062960_v53_n10_p1680_Chemes2023-06-08T14:30:48Z Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles Chemes, Lucía Beatriz de Prat Gay, Gonzalo Covalent bonds Proteins Redox reactions Rubidium Tissue culture Zinc Cell transformation Chaperone activity Disulfide bridge Human papillomavirus Oxidative conditions Protective effects Retinoblastoma tumors Structural rearrangement Amino acids Amino Acid Motifs Amino Acid Sequence Cysteine Human papillomavirus 16 Humans Models, Molecular Molecular Sequence Data Oxidative Stress Papillomavirus E7 Proteins Papillomavirus Infections Sequence Alignment Zinc Fingers The E7 protein from high-risk human papillomavirus is essential for cell transformation in cervical, oropharyngeal, and other HPV-related cancers, mainly through the inactivation of the retinoblastoma (Rb) tumor suppressor. Its high cysteine content (∼7%) and the observation that HPV-transformed cells are under oxidative stress prompted us to investigate the redox properties of the HPV16 E7 protein under biologically compatible oxidative conditions. The seven cysteines in HPV16 E7 remain reduced in conditions resembling the basal reduced state of a cell. However, under oxidative stress, a stable disulfide bridge forms between cysteines 59 and 68. Residue 59 has a protective effect on the other cysteines, and its mutation leads to an overall increase in the oxidation propensity of E7, including cysteine 24 central to the Rb binding motif. Gluthationylation of Cys 24 abolishes Rb binding, which is reversibly recovered upon reduction. Cysteines 59 and 68 are located 18.6 Å apart, and the formation of the disulfide bridge leads to a large structural rearrangement while retaining strong Zn association. These conformational and covalent changes are fully reversible upon restoration of the reductive environment. In addition, this is the first evidence of an interaction between the N-terminal intrinsically disordered and the C-terminal globular domains, known to be highly and separately conserved among human papillomaviruses. The significant conservation of such noncanonical cysteines in HPV E7 proteins leads us to propose a functional redox activity. Such an activity adds to the previously discovered chaperone activity of E7 and supports the picture of a moonlighting pathological role of this paradigmatic viral oncoprotein. © 2014 American Chemical Society. Fil:Chemes, L.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:De Prat-Gay, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v53_n10_p1680_Chemes http://hdl.handle.net/20.500.12110/paper_00062960_v53_n10_p1680_Chemes |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Covalent bonds Proteins Redox reactions Rubidium Tissue culture Zinc Cell transformation Chaperone activity Disulfide bridge Human papillomavirus Oxidative conditions Protective effects Retinoblastoma tumors Structural rearrangement Amino acids Amino Acid Motifs Amino Acid Sequence Cysteine Human papillomavirus 16 Humans Models, Molecular Molecular Sequence Data Oxidative Stress Papillomavirus E7 Proteins Papillomavirus Infections Sequence Alignment Zinc Fingers |
| spellingShingle |
Covalent bonds Proteins Redox reactions Rubidium Tissue culture Zinc Cell transformation Chaperone activity Disulfide bridge Human papillomavirus Oxidative conditions Protective effects Retinoblastoma tumors Structural rearrangement Amino acids Amino Acid Motifs Amino Acid Sequence Cysteine Human papillomavirus 16 Humans Models, Molecular Molecular Sequence Data Oxidative Stress Papillomavirus E7 Proteins Papillomavirus Infections Sequence Alignment Zinc Fingers Chemes, Lucía Beatriz de Prat Gay, Gonzalo Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles |
| topic_facet |
Covalent bonds Proteins Redox reactions Rubidium Tissue culture Zinc Cell transformation Chaperone activity Disulfide bridge Human papillomavirus Oxidative conditions Protective effects Retinoblastoma tumors Structural rearrangement Amino acids Amino Acid Motifs Amino Acid Sequence Cysteine Human papillomavirus 16 Humans Models, Molecular Molecular Sequence Data Oxidative Stress Papillomavirus E7 Proteins Papillomavirus Infections Sequence Alignment Zinc Fingers |
| description |
The E7 protein from high-risk human papillomavirus is essential for cell transformation in cervical, oropharyngeal, and other HPV-related cancers, mainly through the inactivation of the retinoblastoma (Rb) tumor suppressor. Its high cysteine content (∼7%) and the observation that HPV-transformed cells are under oxidative stress prompted us to investigate the redox properties of the HPV16 E7 protein under biologically compatible oxidative conditions. The seven cysteines in HPV16 E7 remain reduced in conditions resembling the basal reduced state of a cell. However, under oxidative stress, a stable disulfide bridge forms between cysteines 59 and 68. Residue 59 has a protective effect on the other cysteines, and its mutation leads to an overall increase in the oxidation propensity of E7, including cysteine 24 central to the Rb binding motif. Gluthationylation of Cys 24 abolishes Rb binding, which is reversibly recovered upon reduction. Cysteines 59 and 68 are located 18.6 Å apart, and the formation of the disulfide bridge leads to a large structural rearrangement while retaining strong Zn association. These conformational and covalent changes are fully reversible upon restoration of the reductive environment. In addition, this is the first evidence of an interaction between the N-terminal intrinsically disordered and the C-terminal globular domains, known to be highly and separately conserved among human papillomaviruses. The significant conservation of such noncanonical cysteines in HPV E7 proteins leads us to propose a functional redox activity. Such an activity adds to the previously discovered chaperone activity of E7 and supports the picture of a moonlighting pathological role of this paradigmatic viral oncoprotein. © 2014 American Chemical Society. |
| author |
Chemes, Lucía Beatriz de Prat Gay, Gonzalo |
| author_facet |
Chemes, Lucía Beatriz de Prat Gay, Gonzalo |
| author_sort |
Chemes, Lucía Beatriz |
| title |
Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles |
| title_short |
Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles |
| title_full |
Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles |
| title_fullStr |
Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles |
| title_full_unstemmed |
Cysteine-rich positions outside the structural zinc motif of human papillomavirus E7 provide conformational modulation and suggest functional redox roles |
| title_sort |
cysteine-rich positions outside the structural zinc motif of human papillomavirus e7 provide conformational modulation and suggest functional redox roles |
| publishDate |
2014 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v53_n10_p1680_Chemes http://hdl.handle.net/20.500.12110/paper_00062960_v53_n10_p1680_Chemes |
| work_keys_str_mv |
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| _version_ |
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