Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target

The retinoblastoma tumor suppressor (Rb) plays a key role in cell cycle control and is linked to various types of human cancer. Rb binds to the LxCxE motif, present in a number of cellular and viral proteins such as AdE1A, SV40 large T-antigen and human papillomavirus (HPV) E7, all instrumental in r...

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Autores principales:	Chemes, L.B., Sánchez, I.E., De Prat-Gay, G.
Formato:	JOUR
Materias:	intrinsically disordered proteins LxCxE motif phosphorylation retinoblastoma protein viral oncoprotein protein E7 retinoblastoma binding protein virus protein article cancer inhibition cell cycle regulation gene expression Human papillomavirus type 16 molecular recognition priority journal protein conformation protein domain protein motif protein protein interaction protein targeting Simian virus 40 tumor suppressor gene Amino Acid Sequence Kinetics Models, Molecular Molecular Sequence Data Papillomavirus E7 Proteins Protein Binding Retinoblastoma Protein Sequence Homology, Amino Acid Thermodynamics Human papillomavirus
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00222836_v412_n2_p267_Chemes
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00222836_v412_n2_p267_Chemes
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spelling	todo:paper_00222836_v412_n2_p267_Chemes2023-10-03T14:30:22Z Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target Chemes, L.B. Sánchez, I.E. De Prat-Gay, G. intrinsically disordered proteins LxCxE motif phosphorylation retinoblastoma protein viral oncoprotein protein E7 retinoblastoma binding protein virus protein article cancer inhibition cell cycle regulation gene expression Human papillomavirus type 16 molecular recognition priority journal protein conformation protein domain protein motif protein protein interaction protein targeting Simian virus 40 tumor suppressor gene Amino Acid Sequence Kinetics Models, Molecular Molecular Sequence Data Papillomavirus E7 Proteins Protein Binding Retinoblastoma Protein Sequence Homology, Amino Acid Thermodynamics Human papillomavirus The retinoblastoma tumor suppressor (Rb) plays a key role in cell cycle control and is linked to various types of human cancer. Rb binds to the LxCxE motif, present in a number of cellular and viral proteins such as AdE1A, SV40 large T-antigen and human papillomavirus (HPV) E7, all instrumental in revealing fundamental mechanisms of tumor suppression, cell cycle control and gene expression. A detailed kinetic study of RbAB binding to the HPV E7 oncoprotein shows that an LxCxE-containing E7 fragment binds through a fast two-state reaction strongly favored by electrostatic interactions. Conversely, full-length E7 binds through a multistep process involving a pre-equilibrium between E7 conformers, a fast electrostatically driven association step guided by the LxCxE motif and a slow conformational rearrangement. This kinetic complexity arises from the conformational plasticity and intrinsically disordered nature of E7 and from multiple interaction surfaces present in both proteins. Affinity differences between E7N domains from high- and low-risk types are explained by their dissociation rates. In fact, since Rb is at the center of a large protein interaction network, fast and tight recognition provides an advantage for disruption by the viral proteins, where the balance of physiological and pathological interactions is dictated by kinetic ligand competition. The localization of the LxCxE motif within an intrinsically disordered domain provides the fast, diffusion-controlled interaction that allows viral proteins to outcompete physiological targets. We describe the interaction mechanism of Rb with a protein ligand, at the same time an LxCxE-containing model target, and a paradigmatic intrinsically disordered viral oncoprotein. © 2011 Elsevier Ltd. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00222836_v412_n2_p267_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	intrinsically disordered proteins LxCxE motif phosphorylation retinoblastoma protein viral oncoprotein protein E7 retinoblastoma binding protein virus protein article cancer inhibition cell cycle regulation gene expression Human papillomavirus type 16 molecular recognition priority journal protein conformation protein domain protein motif protein protein interaction protein targeting Simian virus 40 tumor suppressor gene Amino Acid Sequence Kinetics Models, Molecular Molecular Sequence Data Papillomavirus E7 Proteins Protein Binding Retinoblastoma Protein Sequence Homology, Amino Acid Thermodynamics Human papillomavirus
spellingShingle	intrinsically disordered proteins LxCxE motif phosphorylation retinoblastoma protein viral oncoprotein protein E7 retinoblastoma binding protein virus protein article cancer inhibition cell cycle regulation gene expression Human papillomavirus type 16 molecular recognition priority journal protein conformation protein domain protein motif protein protein interaction protein targeting Simian virus 40 tumor suppressor gene Amino Acid Sequence Kinetics Models, Molecular Molecular Sequence Data Papillomavirus E7 Proteins Protein Binding Retinoblastoma Protein Sequence Homology, Amino Acid Thermodynamics Human papillomavirus Chemes, L.B. Sánchez, I.E. De Prat-Gay, G. Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
topic_facet	intrinsically disordered proteins LxCxE motif phosphorylation retinoblastoma protein viral oncoprotein protein E7 retinoblastoma binding protein virus protein article cancer inhibition cell cycle regulation gene expression Human papillomavirus type 16 molecular recognition priority journal protein conformation protein domain protein motif protein protein interaction protein targeting Simian virus 40 tumor suppressor gene Amino Acid Sequence Kinetics Models, Molecular Molecular Sequence Data Papillomavirus E7 Proteins Protein Binding Retinoblastoma Protein Sequence Homology, Amino Acid Thermodynamics Human papillomavirus
description	The retinoblastoma tumor suppressor (Rb) plays a key role in cell cycle control and is linked to various types of human cancer. Rb binds to the LxCxE motif, present in a number of cellular and viral proteins such as AdE1A, SV40 large T-antigen and human papillomavirus (HPV) E7, all instrumental in revealing fundamental mechanisms of tumor suppression, cell cycle control and gene expression. A detailed kinetic study of RbAB binding to the HPV E7 oncoprotein shows that an LxCxE-containing E7 fragment binds through a fast two-state reaction strongly favored by electrostatic interactions. Conversely, full-length E7 binds through a multistep process involving a pre-equilibrium between E7 conformers, a fast electrostatically driven association step guided by the LxCxE motif and a slow conformational rearrangement. This kinetic complexity arises from the conformational plasticity and intrinsically disordered nature of E7 and from multiple interaction surfaces present in both proteins. Affinity differences between E7N domains from high- and low-risk types are explained by their dissociation rates. In fact, since Rb is at the center of a large protein interaction network, fast and tight recognition provides an advantage for disruption by the viral proteins, where the balance of physiological and pathological interactions is dictated by kinetic ligand competition. The localization of the LxCxE motif within an intrinsically disordered domain provides the fast, diffusion-controlled interaction that allows viral proteins to outcompete physiological targets. We describe the interaction mechanism of Rb with a protein ligand, at the same time an LxCxE-containing model target, and a paradigmatic intrinsically disordered viral oncoprotein. © 2011 Elsevier Ltd.
format	JOUR
author	Chemes, L.B. Sánchez, I.E. De Prat-Gay, G.
author_facet	Chemes, L.B. Sánchez, I.E. De Prat-Gay, G.
author_sort	Chemes, L.B.
title	Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
title_short	Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
title_full	Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
title_fullStr	Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
title_full_unstemmed	Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
title_sort	kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
url	http://hdl.handle.net/20.500.12110/paper_00222836_v412_n2_p267_Chemes
work_keys_str_mv	AT chemeslb kineticrecognitionoftheretinoblastomatumorsuppressorbyaspecificproteintarget AT sanchezie kineticrecognitionoftheretinoblastomatumorsuppressorbyaspecificproteintarget AT depratgayg kineticrecognitionoftheretinoblastomatumorsuppressorbyaspecificproteintarget
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Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target

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