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Abstract:

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.

Registro:

Documento: Artículo
Título:Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target
Autor:Chemes, L.B.; Sánchez, I.E.; De Prat-Gay, G.
Filiación:Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir, IIBBA-CONICET, Avenida Patricias Argentinas 435, 1405 Buenos Aires, Argentina
Protein Physiology Laboratory, Departamento de Quimica Biologica, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina
Palabras clave: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
Año:2011
Volumen:412
Número:2
Página de inicio:267
Página de fin:284
DOI: http://dx.doi.org/10.1016/j.jmb.2011.07.015
Título revista:Journal of Molecular Biology
Título revista abreviado:J. Mol. Biol.
ISSN:00222836
CODEN:JMOBA
CAS:Papillomavirus E7 Proteins; Retinoblastoma Protein; oncogene protein E7, Human papillomavirus type 16
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222836_v412_n2_p267_Chemes

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Citas:

---------- APA ----------
Chemes, L.B., Sánchez, I.E. & De Prat-Gay, G. (2011) . Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target. Journal of Molecular Biology, 412(2), 267-284.
http://dx.doi.org/10.1016/j.jmb.2011.07.015
---------- CHICAGO ----------
Chemes, L.B., Sánchez, I.E., De Prat-Gay, G. "Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target" . Journal of Molecular Biology 412, no. 2 (2011) : 267-284.
http://dx.doi.org/10.1016/j.jmb.2011.07.015
---------- MLA ----------
Chemes, L.B., Sánchez, I.E., De Prat-Gay, G. "Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target" . Journal of Molecular Biology, vol. 412, no. 2, 2011, pp. 267-284.
http://dx.doi.org/10.1016/j.jmb.2011.07.015
---------- VANCOUVER ----------
Chemes, L.B., Sánchez, I.E., De Prat-Gay, G. Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target. J. Mol. Biol. 2011;412(2):267-284.
http://dx.doi.org/10.1016/j.jmb.2011.07.015