Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein

Autores
Chemes, Lucia Beatriz; Sánchez Miguel, Ignacio Enrique; Smal, Clara; de Prat Gay, Gonzalo
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
DNA tumor viruses ensure genome amplification by hijacking the cellular replication machinery and forcing infected cells to enter the S phase. The retinoblastoma (Rb) protein controls the G1/S checkpoint, and is targeted by several viral oncoproteins, among these the E7 protein from human papillomaviruses. A quantitative investigation of the interaction mechanism between the HPV16 E7 protein and the RbAB domain in solution revealed that 90% of the binding energy is determined by the LxCxE motif, with an additional binding determinant (1.0 kcal·mol-1) located in the C-terminal domain of E7, establishing a dual-contact mode. The stoichiometry and subnanomolar affinity of E7 indicate that it can bind RbAB as a monomer. The low-risk HPV11 E7 protein binds 2.0 kcal·mol-1 weaker than the high-risk 16 and 18 type counterparts, but the modularity and binding mode are conserved. Phosphorylation at a conserved casein kinase II site in the natively unfolded N-terminal domain of E7 affects the local conformation by increasing the polyproline II content and stabilizing an extended conformation, which allows for a tighter interaction with Rb. Thus, the E7-RbAB interaction involves multiple motifs within the N-terminal domain of E7 and at least two conserved interaction surfaces in RbAB. We discuss a mechanistic model of the interaction of Rb with a viral target in solution, integrated with structural data and the analysis of other cellular and viral proteins, which provides information about the balance of interactions involving Rb and how these determine the progression into either normal cell cycle or transformation.
Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Smal, Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: de Prat Gay, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Materia
LxCxE MOTIF
NATiVELY UNFOLDED PROTEINS
PHOSPHORYLATION
RETINOBLASTOMA PROTEIN
VIRAL ONCOPROTEIN
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/277380
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/277380
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoproteinChemes, Lucia BeatrizSánchez Miguel, Ignacio EnriqueSmal, Clarade Prat Gay, GonzaloLxCxE MOTIFNATiVELY UNFOLDED PROTEINSPHOSPHORYLATIONRETINOBLASTOMA PROTEINVIRAL ONCOPROTEINhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1DNA tumor viruses ensure genome amplification by hijacking the cellular replication machinery and forcing infected cells to enter the S phase. The retinoblastoma (Rb) protein controls the G1/S checkpoint, and is targeted by several viral oncoproteins, among these the E7 protein from human papillomaviruses. A quantitative investigation of the interaction mechanism between the HPV16 E7 protein and the RbAB domain in solution revealed that 90% of the binding energy is determined by the LxCxE motif, with an additional binding determinant (1.0 kcal·mol-1) located in the C-terminal domain of E7, establishing a dual-contact mode. The stoichiometry and subnanomolar affinity of E7 indicate that it can bind RbAB as a monomer. The low-risk HPV11 E7 protein binds 2.0 kcal·mol-1 weaker than the high-risk 16 and 18 type counterparts, but the modularity and binding mode are conserved. Phosphorylation at a conserved casein kinase II site in the natively unfolded N-terminal domain of E7 affects the local conformation by increasing the polyproline II content and stabilizing an extended conformation, which allows for a tighter interaction with Rb. Thus, the E7-RbAB interaction involves multiple motifs within the N-terminal domain of E7 and at least two conserved interaction surfaces in RbAB. We discuss a mechanistic model of the interaction of Rb with a viral target in solution, integrated with structural data and the analysis of other cellular and viral proteins, which provides information about the balance of interactions involving Rb and how these determine the progression into either normal cell cycle or transformation.Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Smal, Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: de Prat Gay, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaWiley Blackwell Publishing, Inc2010-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/277380Chemes, Lucia Beatriz; Sánchez Miguel, Ignacio Enrique; Smal, Clara; de Prat Gay, Gonzalo; Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein; Wiley Blackwell Publishing, Inc; Febs Journal; 277; 4; 2-2010; 973-9881742-464XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2009.07540.xinfo:eu-repo/semantics/altIdentifier/doi/10.1111/j.1742-4658.2009.07540.xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-01-14T11:49:33Zoai:ri.conicet.gov.ar:11336/277380instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-01-14 11:49:33.638CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
title Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
spellingShingle Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
Chemes, Lucia Beatriz
LxCxE MOTIF
NATiVELY UNFOLDED PROTEINS
PHOSPHORYLATION
RETINOBLASTOMA PROTEIN
VIRAL ONCOPROTEIN
title_short Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
title_full Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
title_fullStr Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
title_full_unstemmed Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
title_sort Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein
dc.creator.none.fl_str_mv Chemes, Lucia Beatriz
Sánchez Miguel, Ignacio Enrique
Smal, Clara
de Prat Gay, Gonzalo
author Chemes, Lucia Beatriz
author_facet Chemes, Lucia Beatriz
Sánchez Miguel, Ignacio Enrique
Smal, Clara
de Prat Gay, Gonzalo
author_role author
author2 Sánchez Miguel, Ignacio Enrique
Smal, Clara
de Prat Gay, Gonzalo
author2_role author
author
author
dc.subject.none.fl_str_mv LxCxE MOTIF
NATiVELY UNFOLDED PROTEINS
PHOSPHORYLATION
RETINOBLASTOMA PROTEIN
VIRAL ONCOPROTEIN
topic LxCxE MOTIF
NATiVELY UNFOLDED PROTEINS
PHOSPHORYLATION
RETINOBLASTOMA PROTEIN
VIRAL ONCOPROTEIN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv DNA tumor viruses ensure genome amplification by hijacking the cellular replication machinery and forcing infected cells to enter the S phase. The retinoblastoma (Rb) protein controls the G1/S checkpoint, and is targeted by several viral oncoproteins, among these the E7 protein from human papillomaviruses. A quantitative investigation of the interaction mechanism between the HPV16 E7 protein and the RbAB domain in solution revealed that 90% of the binding energy is determined by the LxCxE motif, with an additional binding determinant (1.0 kcal·mol-1) located in the C-terminal domain of E7, establishing a dual-contact mode. The stoichiometry and subnanomolar affinity of E7 indicate that it can bind RbAB as a monomer. The low-risk HPV11 E7 protein binds 2.0 kcal·mol-1 weaker than the high-risk 16 and 18 type counterparts, but the modularity and binding mode are conserved. Phosphorylation at a conserved casein kinase II site in the natively unfolded N-terminal domain of E7 affects the local conformation by increasing the polyproline II content and stabilizing an extended conformation, which allows for a tighter interaction with Rb. Thus, the E7-RbAB interaction involves multiple motifs within the N-terminal domain of E7 and at least two conserved interaction surfaces in RbAB. We discuss a mechanistic model of the interaction of Rb with a viral target in solution, integrated with structural data and the analysis of other cellular and viral proteins, which provides information about the balance of interactions involving Rb and how these determine the progression into either normal cell cycle or transformation.
Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Smal, Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: de Prat Gay, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
description DNA tumor viruses ensure genome amplification by hijacking the cellular replication machinery and forcing infected cells to enter the S phase. The retinoblastoma (Rb) protein controls the G1/S checkpoint, and is targeted by several viral oncoproteins, among these the E7 protein from human papillomaviruses. A quantitative investigation of the interaction mechanism between the HPV16 E7 protein and the RbAB domain in solution revealed that 90% of the binding energy is determined by the LxCxE motif, with an additional binding determinant (1.0 kcal·mol-1) located in the C-terminal domain of E7, establishing a dual-contact mode. The stoichiometry and subnanomolar affinity of E7 indicate that it can bind RbAB as a monomer. The low-risk HPV11 E7 protein binds 2.0 kcal·mol-1 weaker than the high-risk 16 and 18 type counterparts, but the modularity and binding mode are conserved. Phosphorylation at a conserved casein kinase II site in the natively unfolded N-terminal domain of E7 affects the local conformation by increasing the polyproline II content and stabilizing an extended conformation, which allows for a tighter interaction with Rb. Thus, the E7-RbAB interaction involves multiple motifs within the N-terminal domain of E7 and at least two conserved interaction surfaces in RbAB. We discuss a mechanistic model of the interaction of Rb with a viral target in solution, integrated with structural data and the analysis of other cellular and viral proteins, which provides information about the balance of interactions involving Rb and how these determine the progression into either normal cell cycle or transformation.
publishDate 2010
dc.date.none.fl_str_mv 2010-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/277380
Chemes, Lucia Beatriz; Sánchez Miguel, Ignacio Enrique; Smal, Clara; de Prat Gay, Gonzalo; Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein; Wiley Blackwell Publishing, Inc; Febs Journal; 277; 4; 2-2010; 973-988
1742-464X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/277380
identifier_str_mv Chemes, Lucia Beatriz; Sánchez Miguel, Ignacio Enrique; Smal, Clara; de Prat Gay, Gonzalo; Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein; Wiley Blackwell Publishing, Inc; Febs Journal; 277; 4; 2-2010; 973-988
1742-464X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2009.07540.x
info:eu-repo/semantics/altIdentifier/doi/10.1111/j.1742-4658.2009.07540.x
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.211636

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