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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Autor principal: Chemes, L.B
Otros Autores: Sánchez, I.E, De Prat-Gay, G.
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Lenguaje:Inglés
Publicado: 2011
Acceso en línea:Registro en Scopus
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024 7 |2 scopus  |a 2-s2.0-80052021703 
024 7 |2 cas  |a Papillomavirus E7 Proteins; Retinoblastoma Protein; oncogene protein E7, Human papillomavirus type 16 
040 |a Scopus  |b spa  |c AR-BaUEN  |d AR-BaUEN 
030 |a JMOBA 
100 1 |a Chemes, L.B. 
245 1 0 |a Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target 
260 |c 2011 
270 1 0 |m De Prat-Gay, G.; Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir, IIBBA-CONICET, Avenida Patricias Argentinas 435, 1405 Buenos Aires, Argentina; email: gpg@leloir.org.ar 
506 |2 openaire  |e Política editorial 
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520 3 |a 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.  |l eng 
536 |a Detalles de la financiación: Consejo Nacional de Investigaciones Científicas y Técnicas 
536 |a Detalles de la financiación: Fundación YPF 
536 |a Detalles de la financiación: L.B.C. currently holds a postdoctoral fellowship from Consejo Nacional de Investigaciones Científicas y Técnicas and was supported throughout the work by a José A. Estenssoro predoctoral fellowship from Fundación YPF . I.E.S. and G.d.P.-G. are career investigators from Consejo Nacional de Investigaciones Científicas y Técnicas. We thank M. Trevisan for helpful advice on quantitative modeling of the E7:Rb interaction. Appendix A 
593 |a Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir, IIBBA-CONICET, Avenida Patricias Argentinas 435, 1405 Buenos Aires, Argentina 
593 |a Protein Physiology Laboratory, Departamento de Quimica Biologica, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina 
690 1 0 |a INTRINSICALLY DISORDERED PROTEINS 
690 1 0 |a LXCXE MOTIF 
690 1 0 |a PHOSPHORYLATION 
690 1 0 |a RETINOBLASTOMA PROTEIN 
690 1 0 |a VIRAL ONCOPROTEIN 
690 1 0 |a PROTEIN E7 
690 1 0 |a RETINOBLASTOMA BINDING PROTEIN 
690 1 0 |a VIRUS PROTEIN 
690 1 0 |a ARTICLE 
690 1 0 |a CANCER INHIBITION 
690 1 0 |a CELL CYCLE REGULATION 
690 1 0 |a GENE EXPRESSION 
690 1 0 |a HUMAN PAPILLOMAVIRUS TYPE 16 
690 1 0 |a MOLECULAR RECOGNITION 
690 1 0 |a PRIORITY JOURNAL 
690 1 0 |a PROTEIN CONFORMATION 
690 1 0 |a PROTEIN DOMAIN 
690 1 0 |a PROTEIN MOTIF 
690 1 0 |a PROTEIN PROTEIN INTERACTION 
690 1 0 |a PROTEIN TARGETING 
690 1 0 |a SIMIAN VIRUS 40 
690 1 0 |a TUMOR SUPPRESSOR GENE 
690 1 0 |a AMINO ACID SEQUENCE 
690 1 0 |a KINETICS 
690 1 0 |a MODELS, MOLECULAR 
690 1 0 |a MOLECULAR SEQUENCE DATA 
690 1 0 |a PAPILLOMAVIRUS E7 PROTEINS 
690 1 0 |a PROTEIN BINDING 
690 1 0 |a RETINOBLASTOMA PROTEIN 
690 1 0 |a SEQUENCE HOMOLOGY, AMINO ACID 
690 1 0 |a THERMODYNAMICS 
690 1 0 |a HUMAN PAPILLOMAVIRUS 
700 1 |a Sánchez, I.E. 
700 1 |a De Prat-Gay, G. 
773 0 |d 2011  |g v. 412  |h pp. 267-284  |k n. 2  |p J. Mol. Biol.  |x 00222836  |w (AR-BaUEN)CENRE-1757  |t Journal of Molecular Biology 
856 4 1 |u https://www.scopus.com/inward/record.uri?eid=2-s2.0-80052021703&doi=10.1016%2fj.jmb.2011.07.015&partnerID=40&md5=85c19821f32d4427ea6e6ae3a51596fe  |y Registro en Scopus 
856 4 0 |u https://doi.org/10.1016/j.jmb.2011.07.015  |y DOI 
856 4 0 |u https://hdl.handle.net/20.500.12110/paper_00222836_v412_n2_p267_Chemes  |y Handle 
856 4 0 |u https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222836_v412_n2_p267_Chemes  |y Registro en la Biblioteca Digital 
961 |a paper_00222836_v412_n2_p267_Chemes  |b paper  |c PE 
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999 |c 84570