Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation

Autores
Padilla Franzotti, Carla Luciana; Palopoli, Nicolás; Palma, Juliana Isabel; Pierdominici Sottile, Gustavo
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Introduction: The retinoblastoma protein (pRb) is a key regulator of the cell cycle that suppresses cell proliferation by binding to E2F transcription factors. Disruption of this pathway, commonly through mutations or interactions with viral oncoproteins, can lead to uncontrolled cell growth and cancer. The large T antigen of simian virus 40 (LTSV40) is known to bind pRb, thereby inhibiting its interaction with E2F transcription factors. However, the structural and dynamic mechanisms underlying this inhibition remain incompletely understood. Methods: We employed molecular dynamics (MD) simulations, principal component analysis, and cluster analysis to investigate the conformational dynamics of pRb, LTSV40, and their complex. Our study focused on an intrinsically disordered region on the C-terminal side of the LFCSE motif of LTSV40, referred to as Linker 1. Results: Our simulations reveal that Linker 1 undergoes a significant conformational shift upon binding to pRb. While this region adopts a predominantly bent structure in the unbound state, it transitions into an extended conformation in the complex. As a consequence of this change, the C-terminal segment of LTSV40 obstructs access to the AB-cleft of pRb, the binding site for E2F. Discussion: Our findings suggest that the inactivation mechanism of pRb by LTSV40, as unveiled by MD simulations, could represent a broader strategy employed by other viral oncoproteins containing similar LXCXE motifs and adjacent disordered regions. This mechanism may even extend to endogenous pRb inactivation. As our conclusions are based on computational modeling, they require experimental validation. Such confirmation would pave the way for developing therapeutic strategies aimed at reactivating pRb function in pathologies where it is compromised.
Fil: Padilla Franzotti, Carla Luciana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Palopoli, Nicolás. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Palma, Juliana Isabel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pierdominici Sottile, Gustavo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Intrinsically disorder proteins
Retinoblastoma protein
Molecular dynamics
Oncogenic proteins
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:11336/265553
Acceder
id CONICETDig_17b6fbaee11904263c46b66c406d1cd2
oai_identifier_str oai:ri.conicet.gov.ar:11336/265553
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivationPadilla Franzotti, Carla LucianaPalopoli, NicolásPalma, Juliana IsabelPierdominici Sottile, GustavoIntrinsically disorder proteinsRetinoblastoma proteinMolecular dynamicsOncogenic proteinshttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Introduction: The retinoblastoma protein (pRb) is a key regulator of the cell cycle that suppresses cell proliferation by binding to E2F transcription factors. Disruption of this pathway, commonly through mutations or interactions with viral oncoproteins, can lead to uncontrolled cell growth and cancer. The large T antigen of simian virus 40 (LTSV40) is known to bind pRb, thereby inhibiting its interaction with E2F transcription factors. However, the structural and dynamic mechanisms underlying this inhibition remain incompletely understood. Methods: We employed molecular dynamics (MD) simulations, principal component analysis, and cluster analysis to investigate the conformational dynamics of pRb, LTSV40, and their complex. Our study focused on an intrinsically disordered region on the C-terminal side of the LFCSE motif of LTSV40, referred to as Linker 1. Results: Our simulations reveal that Linker 1 undergoes a significant conformational shift upon binding to pRb. While this region adopts a predominantly bent structure in the unbound state, it transitions into an extended conformation in the complex. As a consequence of this change, the C-terminal segment of LTSV40 obstructs access to the AB-cleft of pRb, the binding site for E2F. Discussion: Our findings suggest that the inactivation mechanism of pRb by LTSV40, as unveiled by MD simulations, could represent a broader strategy employed by other viral oncoproteins containing similar LXCXE motifs and adjacent disordered regions. This mechanism may even extend to endogenous pRb inactivation. As our conclusions are based on computational modeling, they require experimental validation. Such confirmation would pave the way for developing therapeutic strategies aimed at reactivating pRb function in pathologies where it is compromised.Fil: Padilla Franzotti, Carla Luciana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Palopoli, Nicolás. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Palma, Juliana Isabel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pierdominici Sottile, Gustavo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFrontiers Media2025-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/265553Padilla Franzotti, Carla Luciana; Palopoli, Nicolás; Palma, Juliana Isabel; Pierdominici Sottile, Gustavo; Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation; Frontiers Media; Frontiers in Chemical Biology; 4; 4-2025; 1-132813-530XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fchbi.2025.1538350/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fchbi.2025.1538350info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:58:38Zoai:ri.conicet.gov.ar:11336/265553instacron: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:34982025-10-15 14:58:38.535CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
title Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
spellingShingle Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
Padilla Franzotti, Carla Luciana
Intrinsically disorder proteins
Retinoblastoma protein
Molecular dynamics
Oncogenic proteins
title_short Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
title_full Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
title_fullStr Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
title_full_unstemmed Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
title_sort Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
dc.creator.none.fl_str_mv Padilla Franzotti, Carla Luciana
Palopoli, Nicolás
Palma, Juliana Isabel
Pierdominici Sottile, Gustavo
author Padilla Franzotti, Carla Luciana
author_facet Padilla Franzotti, Carla Luciana
Palopoli, Nicolás
Palma, Juliana Isabel
Pierdominici Sottile, Gustavo
author_role author
author2 Palopoli, Nicolás
Palma, Juliana Isabel
Pierdominici Sottile, Gustavo
author2_role author
author
author
dc.subject.none.fl_str_mv Intrinsically disorder proteins
Retinoblastoma protein
Molecular dynamics
Oncogenic proteins
topic Intrinsically disorder proteins
Retinoblastoma protein
Molecular dynamics
Oncogenic proteins
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Introduction: The retinoblastoma protein (pRb) is a key regulator of the cell cycle that suppresses cell proliferation by binding to E2F transcription factors. Disruption of this pathway, commonly through mutations or interactions with viral oncoproteins, can lead to uncontrolled cell growth and cancer. The large T antigen of simian virus 40 (LTSV40) is known to bind pRb, thereby inhibiting its interaction with E2F transcription factors. However, the structural and dynamic mechanisms underlying this inhibition remain incompletely understood. Methods: We employed molecular dynamics (MD) simulations, principal component analysis, and cluster analysis to investigate the conformational dynamics of pRb, LTSV40, and their complex. Our study focused on an intrinsically disordered region on the C-terminal side of the LFCSE motif of LTSV40, referred to as Linker 1. Results: Our simulations reveal that Linker 1 undergoes a significant conformational shift upon binding to pRb. While this region adopts a predominantly bent structure in the unbound state, it transitions into an extended conformation in the complex. As a consequence of this change, the C-terminal segment of LTSV40 obstructs access to the AB-cleft of pRb, the binding site for E2F. Discussion: Our findings suggest that the inactivation mechanism of pRb by LTSV40, as unveiled by MD simulations, could represent a broader strategy employed by other viral oncoproteins containing similar LXCXE motifs and adjacent disordered regions. This mechanism may even extend to endogenous pRb inactivation. As our conclusions are based on computational modeling, they require experimental validation. Such confirmation would pave the way for developing therapeutic strategies aimed at reactivating pRb function in pathologies where it is compromised.
Fil: Padilla Franzotti, Carla Luciana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Palopoli, Nicolás. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Palma, Juliana Isabel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pierdominici Sottile, Gustavo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Introduction: The retinoblastoma protein (pRb) is a key regulator of the cell cycle that suppresses cell proliferation by binding to E2F transcription factors. Disruption of this pathway, commonly through mutations or interactions with viral oncoproteins, can lead to uncontrolled cell growth and cancer. The large T antigen of simian virus 40 (LTSV40) is known to bind pRb, thereby inhibiting its interaction with E2F transcription factors. However, the structural and dynamic mechanisms underlying this inhibition remain incompletely understood. Methods: We employed molecular dynamics (MD) simulations, principal component analysis, and cluster analysis to investigate the conformational dynamics of pRb, LTSV40, and their complex. Our study focused on an intrinsically disordered region on the C-terminal side of the LFCSE motif of LTSV40, referred to as Linker 1. Results: Our simulations reveal that Linker 1 undergoes a significant conformational shift upon binding to pRb. While this region adopts a predominantly bent structure in the unbound state, it transitions into an extended conformation in the complex. As a consequence of this change, the C-terminal segment of LTSV40 obstructs access to the AB-cleft of pRb, the binding site for E2F. Discussion: Our findings suggest that the inactivation mechanism of pRb by LTSV40, as unveiled by MD simulations, could represent a broader strategy employed by other viral oncoproteins containing similar LXCXE motifs and adjacent disordered regions. This mechanism may even extend to endogenous pRb inactivation. As our conclusions are based on computational modeling, they require experimental validation. Such confirmation would pave the way for developing therapeutic strategies aimed at reactivating pRb function in pathologies where it is compromised.
publishDate 2025
dc.date.none.fl_str_mv 2025-04
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/11336/265553
Padilla Franzotti, Carla Luciana; Palopoli, Nicolás; Palma, Juliana Isabel; Pierdominici Sottile, Gustavo; Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation; Frontiers Media; Frontiers in Chemical Biology; 4; 4-2025; 1-13
2813-530X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/265553
identifier_str_mv Padilla Franzotti, Carla Luciana; Palopoli, Nicolás; Palma, Juliana Isabel; Pierdominici Sottile, Gustavo; Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation; Frontiers Media; Frontiers in Chemical Biology; 4; 4-2025; 1-13
2813-530X
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://www.frontiersin.org/articles/10.3389/fchbi.2025.1538350/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fchbi.2025.1538350
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
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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
_version_ 1846083127161651200
score 13.22299

Publicaciones similares