Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain

Autores
Chemes, Lucia Beatriz; Noval, María Gabriela; Sánchez Miguel, Ignacio Enrique; de Prat Gay, Gonzalo
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high conservation of the Rb cyclin fold prompted us to investigate the link between conformational stability and ligand binding properties of the RbAB pocket domain. RbAB unfolding presents a three-state transition involving cooperative secondary and tertiary structure changes and a partially folded intermediate that can oligomerize. The first transition corresponds to unfolding of the metastable B subdomain containing the binding site for the LXCXE motif present in cellular and viral targets, and the second transition corresponds to the stable A subdomain. The low thermodynamic stability of RbAB translates into a propensity to rapidly oligomerize and aggregate at 37 °C (T50 = 28 min) that is suppressed by human papillomavirus E7 and E2F peptide ligands, suggesting that Rb is likely stabilized in vivo through binding to target proteins. We propose that marginal stability and associated oligomerization may be conserved for function as a "hub" protein, allowing the formation of multiprotein complexes, which could constitute a robust mechanism to retain its cell cycle regulatory role throughout evolution. Decreased stability and oligomerization are shared with the p53 tumor suppressor, suggesting a link between folding and function in these two essential cell regulators that are inactivated in most cancers and operate within multitarget signaling pathways.
Fil: Chemes, Lucia Beatriz. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Noval, María Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: de Prat Gay, Gonzalo. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Materia
Retinoblastoma
tumor suppressor
protein folding
protein misfolding
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:11336/15267
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/15267
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domainChemes, Lucia BeatrizNoval, María GabrielaSánchez Miguel, Ignacio Enriquede Prat Gay, GonzaloRetinoblastomatumor suppressorprotein foldingprotein misfoldinghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high conservation of the Rb cyclin fold prompted us to investigate the link between conformational stability and ligand binding properties of the RbAB pocket domain. RbAB unfolding presents a three-state transition involving cooperative secondary and tertiary structure changes and a partially folded intermediate that can oligomerize. The first transition corresponds to unfolding of the metastable B subdomain containing the binding site for the LXCXE motif present in cellular and viral targets, and the second transition corresponds to the stable A subdomain. The low thermodynamic stability of RbAB translates into a propensity to rapidly oligomerize and aggregate at 37 °C (T50 = 28 min) that is suppressed by human papillomavirus E7 and E2F peptide ligands, suggesting that Rb is likely stabilized in vivo through binding to target proteins. We propose that marginal stability and associated oligomerization may be conserved for function as a "hub" protein, allowing the formation of multiprotein complexes, which could constitute a robust mechanism to retain its cell cycle regulatory role throughout evolution. Decreased stability and oligomerization are shared with the p53 tumor suppressor, suggesting a link between folding and function in these two essential cell regulators that are inactivated in most cancers and operate within multitarget signaling pathways.Fil: Chemes, Lucia Beatriz. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Noval, María Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: de Prat Gay, Gonzalo. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaAmerican Society For Biochemistry And Molecular Biology2013-06info: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/11336/15267Chemes, Lucia Beatriz; Noval, María Gabriela; Sánchez Miguel, Ignacio Enrique; de Prat Gay, Gonzalo; Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain; American Society For Biochemistry And Molecular Biology; Journal Of Biological Chemistry; 288; 26; 6-2013; 18923-189381083-351Xenginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/288/26/18923.longinfo:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M113.467316info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:07Zoai:ri.conicet.gov.ar:11336/15267instacron: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:34982025-09-03 10:05:07.572CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
title Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
spellingShingle Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
Chemes, Lucia Beatriz
Retinoblastoma
tumor suppressor
protein folding
protein misfolding
title_short Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
title_full Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
title_fullStr Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
title_full_unstemmed Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
title_sort Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain
dc.creator.none.fl_str_mv Chemes, Lucia Beatriz
Noval, María Gabriela
Sánchez Miguel, Ignacio Enrique
de Prat Gay, Gonzalo
author Chemes, Lucia Beatriz
author_facet Chemes, Lucia Beatriz
Noval, María Gabriela
Sánchez Miguel, Ignacio Enrique
de Prat Gay, Gonzalo
author_role author
author2 Noval, María Gabriela
Sánchez Miguel, Ignacio Enrique
de Prat Gay, Gonzalo
author2_role author
author
author
dc.subject.none.fl_str_mv Retinoblastoma
tumor suppressor
protein folding
protein misfolding
topic Retinoblastoma
tumor suppressor
protein folding
protein misfolding
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high conservation of the Rb cyclin fold prompted us to investigate the link between conformational stability and ligand binding properties of the RbAB pocket domain. RbAB unfolding presents a three-state transition involving cooperative secondary and tertiary structure changes and a partially folded intermediate that can oligomerize. The first transition corresponds to unfolding of the metastable B subdomain containing the binding site for the LXCXE motif present in cellular and viral targets, and the second transition corresponds to the stable A subdomain. The low thermodynamic stability of RbAB translates into a propensity to rapidly oligomerize and aggregate at 37 °C (T50 = 28 min) that is suppressed by human papillomavirus E7 and E2F peptide ligands, suggesting that Rb is likely stabilized in vivo through binding to target proteins. We propose that marginal stability and associated oligomerization may be conserved for function as a "hub" protein, allowing the formation of multiprotein complexes, which could constitute a robust mechanism to retain its cell cycle regulatory role throughout evolution. Decreased stability and oligomerization are shared with the p53 tumor suppressor, suggesting a link between folding and function in these two essential cell regulators that are inactivated in most cancers and operate within multitarget signaling pathways.
Fil: Chemes, Lucia Beatriz. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Noval, María Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: de Prat Gay, Gonzalo. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
description The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high conservation of the Rb cyclin fold prompted us to investigate the link between conformational stability and ligand binding properties of the RbAB pocket domain. RbAB unfolding presents a three-state transition involving cooperative secondary and tertiary structure changes and a partially folded intermediate that can oligomerize. The first transition corresponds to unfolding of the metastable B subdomain containing the binding site for the LXCXE motif present in cellular and viral targets, and the second transition corresponds to the stable A subdomain. The low thermodynamic stability of RbAB translates into a propensity to rapidly oligomerize and aggregate at 37 °C (T50 = 28 min) that is suppressed by human papillomavirus E7 and E2F peptide ligands, suggesting that Rb is likely stabilized in vivo through binding to target proteins. We propose that marginal stability and associated oligomerization may be conserved for function as a "hub" protein, allowing the formation of multiprotein complexes, which could constitute a robust mechanism to retain its cell cycle regulatory role throughout evolution. Decreased stability and oligomerization are shared with the p53 tumor suppressor, suggesting a link between folding and function in these two essential cell regulators that are inactivated in most cancers and operate within multitarget signaling pathways.
publishDate 2013
dc.date.none.fl_str_mv 2013-06
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/11336/15267
Chemes, Lucia Beatriz; Noval, María Gabriela; Sánchez Miguel, Ignacio Enrique; de Prat Gay, Gonzalo; Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain; American Society For Biochemistry And Molecular Biology; Journal Of Biological Chemistry; 288; 26; 6-2013; 18923-18938
1083-351X
url http://hdl.handle.net/11336/15267
identifier_str_mv Chemes, Lucia Beatriz; Noval, María Gabriela; Sánchez Miguel, Ignacio Enrique; de Prat Gay, Gonzalo; Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain; American Society For Biochemistry And Molecular Biology; Journal Of Biological Chemistry; 288; 26; 6-2013; 18923-18938
1083-351X
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/288/26/18923.long
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M113.467316
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 American Society For Biochemistry And Molecular Biology
publisher.none.fl_str_mv American Society For Biochemistry And Molecular Biology
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 13.13397

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